TOXICOLOGICAL PROFILE FOR CYANIDE Prepared by: Syracuse Research Corporation Under Subcontract to: Clement International Corporation Under Contract No. 205-838-0608 Prepared for: U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES Public Health Service Agency for Toxic Substances and Disease Registry April 1993 CAT ror PUBLIC HEALPH i DISCLAIMER The use of company or product name(s) is for identification only and does not imply endorsement by the Agency for Toxic Substances and Disease Registry. | H 9 { iii [67 UPDATE STATEMENT ‘os | A ) 1935 A Toxicological Profile for cyanide was released on December 1989. This edition supersedes any previously Dive released draft or final profile. | V C v Toxicological profiles are revised and republished as necessary, but no less than once every three years. For information regarding the update status of previously released profiles, contact ATSDR at: Agency for Toxic Substances and Disease Registry Division of Toxicology/Toxicology Information Branch 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 FOREWORD The Superfund Amendments and Reauthorization Act (SARA) of 1986 (Public Law 99-499) extended and amended the Comprehensive Environmental Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund). This public law directed the Agency for Toxic Substances and Disease Registry (ATSDR) to prepare toxicological profiles for hazardous substances which are most commonly found at facilities on the CERCLA National Priorities List and which pose the most significant potential threat to human health, as determined by ATSDR and the Environmental Protection Agency (EPA). The lists of the 250 most significant hazardous substances were published in the Federal Register on April 17, 1987, on October 20, 1988, on October 26, 1989, on October 17, 1990, and on October 17, 1991. A revised list of 275 substances was published on October 28, 1992. Section 104(i)(3) of CERCLA, as amended, directs the Administrator of ATSDR to prepare a toxicological profile for each substance on the lists. Each profile must include the following: (A) The examination, summary, and interpretation of available toxicological information and epidemiological evaluations on a hazardous substance in order to ascertain the levels of significant human exposure for the substance and the associated acute, subacute, and chronic health effects. (B) A determination of whether adequate information on the health effects of each substance is available or in the process of development to determine levels of exposure which present a significant risk to human health of acute, subacute, and chronic health effects. (C) Where appropriate, identification of toxicological testing needed to identify the types or levels of exposure that may present significant risk of adverse health effects in humans. This toxicological profile is prepared in accordance with guidelines developed by ATSDR and EPA. The original guidelines were published in the Federal Register on April 17, 1987. Each profile will be revised and republished as necessary. The ATSDR toxicological profile is intended to characterize succinctly the toxicological and adverse health effects information for the hazardous substance being described. Each profile identifies and reviews the key literature (that has been peer-reviewed) that describes a hazardous substance’s toxicological properties. Other pertinent literature is also presented but described in less detail than the key studies. The profile is not intended to be an exhaustive document; however, more comprehensive sources of specialty information are referenced. Each toxicological profile begins with a public health statement, which describes in nontechnical language a substance’s relevant toxicological properties. Following the public health statement is information concerning levels of significant human exposure and, where known, significant health effects. The adequacy of information to determine a substance’s health effects is described in a health effects summary. Data needs that are of significance to protection of public health will be identified by ATSDR and EPA. The focus of the profiles is on health and toxicological information; therefore, we have included this information in the beginning of the document. vi Foreword The principal audiences for the toxicological profiles are health professionals at the federal. state. and local levels, interested private sector organizations and groups, and members of the public. This profile reflects our assessment of all relevant toxicological testing and information that has been peer reviewed. It has been reviewed by scientists trom ATSDR, the Centers for Disease Control and Prevention (CDC). and other federal agencies. It has also been reviewed by a panel of nongovernment peer reviewers and is being made available for public review. Final responsibility for the contents and views expressed in this toxicological profile resides with ATSDR. William L. Roper. M.D., Administrator Agency for Toxic Substances and Disease Registry CEE CI A RT SC i EA ARS a ai A Nk ata vii CONTRIBUTORS CHEMICAL MANAGER(S)/AUTHORS(S): Carolyn Harper, Ph.D. ATSDR, Division of Toxicology, Atlanta, GA Fernando Llados, Ph.D. Syracuse Research Corporation, Syracuse, NY Hana Pohl, M.D., Ph.D Syracuse Research Corporation, Syracuse, NY THE PROFILE HAS UNDERGONE THE FOLLOWING ATSDR INTERNAL REVIEWS: 1. Green Border Review. Green Border review assures the consistency with ATSDR policy. Health Effects Review. The Health Effects Review Committee examines the health effects chapter of each profile for consistency and accuracy in interpreting health effects and classifying endpoints. Minimal Risk Level Review. The Minimal Risk Level Workgroup considers issues relevant to substance-specific minimal risk levels (MRLs), reviews the health effects database of each profile, and makes recommendations for derivation of MRLs. Quality Assurance Review. The Quality Assurance Branch assures that consistency across profiles is maintained, identifies any significant problems in format or content, and establishes that Guidance has been followed. CONTENTS FOREWORD .. 5s sini mimo ms53 mau shames 6a festa snsmemensime tines nm wn ad sss v CONTRIBUTORS oie ee ee ee ee eee vii LISTOFFPIGURES . i nin insmvnssnmeunrsiattmsmrsmrwamemomiin na ba bsninsasn xiii LIST OF TABLES . . titties eet ee eee eas Xv 1. PUBLIC HEALTH STATEMENT ..... ie ieee 1 1.1 WHAT IS CYANIDE? . . eee ee 1 1.2 WHAT HAPPENS TO CYANIDE WHEN IT ENTERS THE ENVIRONMENT? . . . .. 2 1.3 HOW MIGHT I BE EXPOSED TO CYANIDE? .......................... 3 1.4 HOW CAN CYANIDE ENTER AND LEAVE MY BODY? ................... 3 1.5 HOW CAN CYANIDE AFFECT MY HEALTH? .......................... 4 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER I HAVE BEEN EXPOSED TO CYANIDE? . . . eee eee 4 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? ....... ie 5 1.8 WHERE CAN I GET MORE INFORMATION? ................. 5 2. HEALTH EFFECTS ... citi iii titi tiie siesta sierra 7 2.1 INTRODUCTION te tee eee eee 7 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE ............ 7 2.2.1 Inhalation EXposure ........... 8 2211 DRAIN ose msnssinem times re rns ras men moma nent 8 22.1.2 Systemic Effects . . ....... Lo 15 2.2.1.3 Immunological Effects ............... 17 2.2.1.4 Neurological Effects . ............... ii 17 2.2.1.5 Developmental Effects .................... 18 2.2.1.6 Reproductive Effects ............... ii 18 2217 QCenotoxiC Effects « .. cc cctv ivr ni msm r sna in tian ns 18 2218 CanClL ....v 019i ds ¥ sd Me CE Ra Gr Hs BIB BI HIB En 14 2a xix wa 18 2.22 Oral EXPOSUIE . «oo tiie 19 2221 Death ..... eee 19 2222 Systemic Effects . . ...... 19 2.2.2.3 Immunological Effects .............. iii 28 2.2.2.4 Neurological Effects . ............. i 28 2.2.2.5 Developmental Effects .................... 29 222.6 Reproductive Effects ................ ci, 30 2227 QCenotoxic Effects ..........ccoutt inne 30 2228 CANCEL vw vv vo vu ta ss bd Fs Bene Mam sR sR AMEN EH SHB tt nem rns 30 2.23 Dermal EXPOSUTE . . o.oo iti 30 223.1 Death ...... eee 30 2232 Systemic Effects . . ........ 31 2.2.3.3 Immunological Effects .............. iii 34 2.2.3.4 Neurological Effects . ............... i 34 2.2.3.5 Developmental Effects .................. 34 2.23.6 Reproductive Effects ................ i iia 34 wn 2237 OCenotOXICEMECES ... coun vuansnionsnsraissmsnsnsmions vo 34 2238 GABF vc scx vs ws R35 500 bd Wik 8k Hk MT BA BE RI rar tn mn 34 23 TOXICOKINETICS . . ee ee ee eee 35 23.1 ADSOIPHON LL oe 35 23.11 Inhalation BXPOSUIC . «. vi cvwrnsusutnamnamsnsmsnensssnm an 35 2312 Oral BEXPOSUIC . vc wi ws movi ss me mem im mu na Re MI mv nama owas 35 23.1.3 Dermal EXpoSUre . . ........ iii 35 23.2 Distribution . . .. Lee 36 232.1 Inhalation EXPOSUIC + « cx vs me ms mom sme m om am sm an se mes ons 36 2322 Oral Baposure . .. cus revnsvs isan nanos annnssmensnsnnso 36 2323 Dermal BXPOSUIC « vi vt vs we me mont ms mom sd ak hk vk 4d hoi someon 37 233 Metabolism . ... LL. 37 23.4 EXCIEtON . o.oo 39 2341 Inhalation EXPOSUIC . vc wt weve mis sat nsmrmom on sn vn oe dessa 39 23427 Oral BXPOSUIC » cw sc sm td vm ps Regan t ms BR im ba a8 Ka dios & 4 4 41 2343 Dermal BXPOSUIC o vv vv vn viv sx vm vm ss as mama moin ad sim aim os ass 41 24 RELEVANCE TO PUBLICHEALTH . ........... iii. 41 2.5 BIOMARKERS OF EXPOSURE AND EFFECT .......................... 49 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Cyanide ............. 51 2.5.2 Biomarkers Used to Characterize Effects Caused by Cyanide .............. 52 2.6 INTERACTIONS WITH OTHER CHEMICALS ........................... 52 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE .................. 54 2.8 METHODS FOR REDUCING TOXIC EFFECTS . ........... oo... 55 2.8.1 Reducing Peak Absorption Following Exposure ....................... 53 282 Reducing Body Burden ...:c:isiusn sui mrosmamastsmonsnmininsnsis 56 2.83 Interfering with the Mechanism of Action for Toxic Effects ............... 56 29 ADEQUACY OF THE DATABASE . . . .. ii 57 2.9.1 Existing Information on Health Effects of Cyanide ..................... 57 292 Identification of Data Needs . . .... cv vs vinrisasnsnannsnsnsnsning 59 293 ON-ZOMZ SIUBIES oot v0 vu vs sous mons somo Hob amos vs snenosorrsne 62 CHEMICAL AND PHYSICAL INFORMATION ............ i... 63 31 CHEMICAL IDENTITY tx vvvrannsusmsnsnsotnsntsns as ss amesscnsns 63 3.2 PHYSICAL AND CHEMICAL PROPERTIES ............................ 63 PRODUCTION, IMPORT, USE, AND DISPOSAL .......... cotinine. 69 41 PRODUCTION ,. uv ncvvoeisn anus ssn tains sminsmon ani asmsdinsis 69 42 IMPORT/EXPORT . . . ee ee eee 69 43 USE 69 4.4 DISPOSAL . . 71 POTENTIAL FOR HUMAN EXPOSURE . ............ ii... 73 5.1 OVERVIEW . 73 5.2 RELEASES TO THE ENVIRONMENT .......... i... 75 B21 All ovine semen min mus se tn 55 95 D4 Rs HINI RI Hr HIE ® 8d 0d wa 75 5200 WASE on :uimyme a imi ida on ts Gum 4 F 5a BI BEB ERE mow om nie sm ns ms 75 B23 BOI cv vi ms vsmemsms mse shai nn tu ms sion sie ma mm mm ren se vy ve 78 53 ENVIRONMENTAL FATE . ... eee 78 53.1 ‘Transport and PAMIONING : «: cso srn un un vans unset nr asm omens s on uss 78 5.3.2 Transformation and Degradation ................................. 79 1 ER 79 xi 327 WAIBT . + vs ttt tsetse nsrssnsisssasanrsssrsasssnssnrenss 79 B53973 BOM «it vn vs vm snes rarer sma tas Rees Err a ae 80 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT ............ 81 SA.1 AIT oo oe ee ee 81 5.42 WALET © ot ee ee ee ee eee eee 81 BAT BOI & vn ct 50 ss vo ttn sme memes Had sh aE si PE HY Sr maa ww eww 82 5.4.4 Other Environmental Media . . . ... «coi 82 55 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE ............... 82 56 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES ................. 83 5.7 ADEQUACY OF THE DATABASE . . . . . ieee ees 84 5.7.1 Identification of Data Needs . . . . . . . «oii iii eee 84 572 On-going Studies ........... cc ivan 86 6. ANALYTICAL METHODS . . . «eee eee ee 87 6.1 BIOLOGICAL MATERIALS . . eee eee eee 87 6.2 ENVIRONMENTAL SAMPLES . . . ie eee 87 63 ADEQUACY OF THE DATABASE . . . «oie ieee eee 95 6.3.1 Identification of Data Needs . . . . . «cuit iii ieee 95 632 On-going Studies . ......... tiie 96 7. REGULATIONS AND ADVISORIES . . . . «eee es 97 8. REFERENCES . © i titi ttt eee ee ee ee ee ee eee eee 101 9. GLOSSARY ©. ttt tt eee 121 APPENDICES A. USER'S GUIDE . . . «i ee ee es eee eee eee A-1 B. ACRONYMS, ABBREVIATIONS, AND SYMBOLS . ................. B-1 C. PEER REVIEW . ote i ieee eee ees C-1 2-1 2-2 2-4 2-5 xiii LIST OF FIGURES Levels of Significant Exposure to Cyanide - Inhalation ............ cove. 13 Levels of Significant Exposure to Cyanide - Oral . .........ovvvvinnnneen 24 Basic Processes Involved in the Metabolism of Cyanide ................ cco. 38 Minor Path for the Removal of Cyanide from the Body .................ovvnvnnn 40 Existing Information on Health Effects of Cyanide ...............oonnnneeeee 58 Frequency of NPL Sites With Cyanide Contamination . . ..... cutie 74 2-1 2-2 2-3 2-4 3-2 4-1 5-1 6-1 6-2 7-1 LIST OF TABLES Levels of Significant Exposure to Cyanide - Inhalation . ........................ 9 Levels of Significant Exposure to Cyanide - Oral . . ..............vn 20 Levels of Significant Exposure to Cyanide - Dermal . . ..............onnn 32 Genotoxicity of Cyanide In Vitro ........... ci 50 Chemical Identity of Cyanide and Compounds... ......... coun nn 64 Physical and Chemical Properties of Cyanide and Compounds ..................... 66 Facilities That Manufacture or Process Cyanide . . . ........ 70 Releases to the Environment From Facilities That Manufacture or Process CYANIIE «sus sr nsmemomospannsanane ia Rsv ans Bs AN ER EBIR RANT nn ws ws 76 Analytical Methods for Determining Cyanide in Biological Materials . ................ 88 Analytical Methods for Determining Cyanide in Environmental Samples .............. 92 Regulations and Guidelines Applicable to Cyanide . . ..........ooonee 98 1. PUBLIC HEALTH STATEMENT This Statement was prepared to give you information about cyanide and to emphasize the human health effects that may result from exposure to it. The Environmental Protection Agency (EPA) has identified 1,300 sites on its National Priorities List (NPL), and cyanide has been found in at least 390 of these sites. However, we do not know how many of the 1,300 NPL sites have been evaluated for cyanide. As EPA evaluates more sites, the number of sites at which cyanide is found may change. This information is important for you to know because cyanide may cause harmful health effects and because these sites are potential or actual sources of human exposure to cyanide. When a chemical is released from a large area, such as an industrial plant, or from a container, such as a drum or bottle, it enters the environment as a chemical emission. This emission, which is also called a release, does not always lead to exposure. You can be exposed to a chemical only when you come into contact with the chemical. You may be exposed to it in the environment by breathing, eating, or drinking substances containing the chemical, or from skin contact with it. If you are exposed to a hazardous chemical such as cyanide, several factors will determine whether harmful health effects will occur and what the type and severity of those health effects will be. These factors include the dose (how much), the duration (how long), the route or pathway by which you are exposed (breathing, eating, drinking, or skin contact), the other chemicals to which you are exposed, and your individual characteristics such as age, sex, nutritional status, family traits, life-style, and state of health. 1.1 WHAT IS CYANIDE? Cyanides are a group of compounds (substances formed by joining two or more chemicals) based on a common structure formed when elemental nitrogen and carbon are combined. Cyanides are produced by certain bacteria, fungi, and algae and may be found in a number of foods and plants. In your body, cyanide can combine with a chemical (hydroxocobalamin) to form vitamin B,, (cyanocobalamin), a vitamin needed in the human diet. Hydrogen cyanide is a compound of cyanide and hydrogen. When cyanide combines with metals and organic compounds (compounds of carbon), it forms simple and complex salts and compounds. Sodium cyanide and potassium cyanide are examples of simple cyanide salts. In cassava rootstocks (potato-like tubers of cassava plants grown in the tropics) and in vitamin B,,, cyanides occur as complex organic compounds. Most cyanide in the soil and water comes from industrial processes. Cyanide salts and hydrogen cyanide are mainly used in electroplating, metallurgy, production of organic chemicals, photographic development, and in the making of plastics. 2 1. PUBLIC HEALTH STATEMENT Cyanide is a powerful and rapid-acting poison. Hydrogen cyanide has been used in gas- chamber executions and as a war gas. Of the cyanide compounds, hydrogen cyanide, sodium cyanide, and potassium cyanide are those most likely to be found in the environment from industrial activities. Hydrogen cyanide is a colorless gas with a faint, bitter, almond-like odor. Sodium cyanide and potassium cyanide are both white solids with a slight, bitter, almond-like odor in damp air. The largest cyanide source in air results from vehicle exhaust. Other sources include releases from certain chemical industries, industrial and municipal waste burning, and the use of cyanide-containing pesticides. The largest cyanide sources in water result from discharges from some metal mining processes, organic chemical industries, iron and steel works, and publicly owned waste water treatment works. Much smaller amounts of cyanide compounds may enter water through storm-water runoff in locations where cyanide-containing road salts are used. Underground water can be contaminated from cyanide present in some landfills. Two incidents of cyanide in soil resulted from the disposal of cyanide-containing wastes in landfills and the use of cyanide-containing road salts. More information on the physical and chemical properties and on the production and use of cyanides can be found in Chapters 3 and 4. 1.2 WHAT HAPPENS TO CYANIDE WHEN IT ENTERS THE ENVIRONMENT? Cyanide enters the air, water, and soil as a result of both natural processes and human activities. The air bound cyanide is generally far below levels of concern. In air, cyanides are present mainly as gaseous hydrogen cyanide. A small amount of cyanide in the air is present as fine dust particles. This dust eventually settles over land and water. Rain and snow aid in removing cyanide particles from the air. The gaseous hydrogen cyanide is not easily removed from the air by settling, rain, or snow. The half-life (the time needed for half of the material to be removed) of hydrogen cyanide in the atmosphere is 1 to 3 years. Most of the cyanides in water will form hydrogen cyanide and evaporate from water. Some of the cyanides in water will be transformed into other less harmful chemicals by microorganisms (organisms of very small size) in the water, or by combining to form a complex with metals, such as iron. Although the exact half-life of cyanide in water is not known, it is expected to be generally shorter than in air. Cyanides in water do not build up in the bodies of fish. A portion of cyanide in soil can form hydrogen cyanide and evaporate. Some of the cyanide will be transformed into other chemical forms by microorganisms in the soil. Some forms of cyanide may remain in soil, but cyanides do not usually seep into underground water. However, cyanides have been detected in underground waters of a few landfills. At the high concentrations found in some landfill leachates (water that seeps through landfill soil), cyanides become toxic to soil microorganisms. Since these microorganisms can no longer transform (change to other chemical forms) cyanides, the cyanides are able to pass through the soil into underground water. More information about the fate and movement of cyanides in the environment can be found in Chapters 4 and 5. 3 1. PUBLIC HEALTH STATEMENT 1.3 HOW MIGHT | BE EXPOSED TO CYANIDE? You may be exposed to cyanides from breathing air and drinking water, touching soil or water containing cyanide, or eating foods that contain cyanides. Many plant materials, such as cassava roots, lima beans, and almonds, contain cyanide compounds at low to moderate concentrations. People who work in cyanide-related industries may be exposed to cyanide by touching cyanide as well. The concentration of hydrogen cyanide in unpolluted air is less than 0.0002 ppm (1 ppm is equivalent to 1 part by volume of hydrogen cyanide in a million parts by volume of air). The concentration range of cyanogen chloride in drinking water, which is formed following water chlorination, is 0.00045 to 0.0008 ppm (1 ppm is equivalent to 1 part by weight in a million parts by volume of water). The total human intake of cyanide from eating foods that naturally contain cyanide is not known. Smoking is probably one of the major sources of cyanide exposure for people who do not work in cyanide-related industries. Breathing smoke-filled air during fires may also be a major source of cyanide exposure. People who live near hazardous waste sites that contain cyanides may also be exposed to higher amounts of cyanides compared with the general population. Cyanides are used or produced in various occupational settings where activities include, but are not limited to, electroplating, some metal mining processes, metallurgy, metal cleaning, certain pesticide applications, tanning, blacksmithing, photography and photoengraving, firefighting, and gas works operations. Cyanides are also used in some dye and pharmaceutical industries and are produced by other cyanide chemical industries. The National Occupational Exposure Survey (NOES) estimated that a total of 3,780 workers are potentially exposed to hydrogen cyanide, 63,584 workers are potentially exposed to sodium cyanide, and 59,225 workers are potentially exposed to potassium cyanide. More information on exposure to cyanide can be found in Chapter 5. 1.4 HOW CAN CYANIDE ENTER AND LEAVE MY BODY? Cyanide can enter your body if you breathe air, eat food, or drink water that contains cyanide. Cyanide can enter your body through the skin, but this exposure route is common only in the workplace. Exposure to contaminated water, air, or soil can occur at hazardous waste sites. Once it is in your body, cyanide can quickly enter the bloodstream. Some of the cyanide is changed to a chemical (thiocyanate) that is not as harmful and leaves the body in the urine. Some of the cyanide that enters your body can also combine with a chemical (hydroxocobalamin) to form vitamin B,,. Some cyanide is converted in the body to carbon dioxide, which is removed from the body in the breath. Most of the cyanide and its products leave the body within the first 24 hours after exposure. The way cyanide enters and leaves the body is similar in humans and animals. You can find more information about the movement of cyanide in the body in Chapter 2. 4 1. PUBLIC HEALTH STATEMENT 1.5 HOW CAN CYANIDE AFFECT MY HEALTH? In large amounts, cyanide is very harmful to your body. The severity of the harmful effects depends in part on the form of the cyanide compounds, such as hydrogen cyanide gas or cyanide salts. Exposure to high levels of cyanide for a short time harms the brain, lungs, and heart, and may even cause coma and death. Individuals who breathed 546 ppm of hydrogen cyanide have died after a 10-minute exposure, 110 ppm hydrogen cyanide was life-threatening after a 1-hour exposure, while exposure to 18 ppm for 1 hour was not harmful. People who eat large amounts of cyanide may die. Some of the first indications of cyanide poisoning are rapid, deep breathing and shortness of breath, followed by convulsions and loss of consciousness. These symptoms can occur rapidly depending on the dose. The health effects of cyanide are similar no matter if large amounts are eaten, drunk, breathed, or touched. Furthermore, skin contact with hydrogen cyanide or cyanide salts can produce skin irritation and sores. Workers who breathed in amounts of hydrogen cyanide as low as 6 to 10 ppm for years had breathing difficulties, pain in the heart area, vomiting, blood changes, headaches, and enlargement of the thyroid gland. Some people in tropical areas who ate cassava roots as the main staple food in their diet had high cyanide levels in their blood. Some of them also suffered harmful effects to the nervous system, including weakness of the fingers and toes, difficulty walking, damaged vision, and deafness, but chemicals other than cyanide may have also contributed to these effects. Cyanide exposure from cassava was also linked to decreased thyroid gland function and goiter development. These effects have not been seen at levels of cyanide exposure usually found in foods in the United States; however, some children who ate apricot pits, which contain organic forms of cyanides, had rapid breathing, low blood pressure, headaches, and coma, and some died. There are no reports that cyanide can cause birth defects or reproductive effects in humans. However, birth defects were seen in rats that ate cassava root diets. Other cyanide effects in animal studies were similar to those observed in humans. There are no reports that cyanide can cause cancer in humans or animals. EPA has determined that cyanide is not classifiable as to its human carcinogenicity. Vitamin B,, is a chemical substance containing cyanide that is beneficial to your body because it prevents anemia, which is iron-poor blood. The cyanide is bound inside the skin so that it does not serve as a source of cyanide exposure and cannot cause harmful effects. You can find more information on the harmful effects of cyanide in Chapter 2. 1.6 IS THERE A MEDICAL TEST TO DETERMINE WHETHER | HAVE BEEN EXPOSED TO CYANIDE? Blood and urine levels of cyanide and thiocyanate, a compound produced from cyanide, can be measured. Because small amounts of these compounds are always in the body, these measurements are only useful when exposure to large amounts of cyanide has occurred. We do not know the exact cyanide exposure levels linked with the levels of cyanide or thiocyanate 5 1. PUBLIC HEALTH STATEMENT in body fluids. Harmful effects can occur when blood levels of cyanide are higher than 0.2 parts per billion (ppb), but the effects may also be associated with lower levels. The measurements for tissue levels of cyanide can be done, if cyanide poisoning is suspected. However, cyanide and thiocyanate are rapidly cleared from the body; therefore, blood measurements can only indicate evidence of recent exposure. An almond-like odor in the breath may alert a physician that a person was exposed to cyanide. For more information regarding the health effects of cyanide and how it can be detected in the environment, please read Chapters 2 and 6. 1.7 WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT HUMAN HEALTH? EPA sets rules for the amount of cyanide in water. The largest amount allowed is 200 micrograms of cyanide per liter of water (ug/L). EPA regulates the amounts of hydrogen cyanide in stored foods that may be treated with cyanide to control pests. The amounts range from 25 ppm in dried beans, peas, and nuts to 250 ppm in spices. Furthermore, EPA requires that industries report spills of 10 pounds or more of hydrogen cyanide, potassium cyanide, or sodium cyanide. The Occupational Safety and Health Administration (OSHA) sets the levels of cyanide that are allowable in workplace air. The permissible exposure limit (PEL) for cyanide salts is 5 milligrams of cyanide per cubic meter of air (mg/m?) averaged over an 8-hour workday, 40-hour workweek. The highest level of hydrogen cyanide that workers may be exposed to for 15 minutes is 4.7 ppm. This is known as the short-term exposure limit (STEL). The STEL for hydrogen cyanide (4.7 ppm) is about the same as 5 mg/m’. OSHA does not set a PEL for hydrogen cyanide. This means that OSHA considers hydrogen cyanide to be more harmful than cyanide salts in the workplace. For more information regarding regulations and advisories for cyanides in the environment or workplace, please read Chapter 7. 1.8 WHERE CAN | GET MORE INFORMATION? If you have any more questions or concerns, please contact your community or state health or environmental quality department or: Agency for Toxic Substances and Disease Registry Division of Toxicology 1600 Clifton Road NE, E-29 Atlanta, Georgia 30333 6 1. PUBLIC HEALTH STATEMENT This agency can also provide you with information on the location of the nearest occupational and environmental health clinic. These clinics specialize in the recognition, evaluation, and treatment of illnesses resulting from exposure to hazardous substances. 2. HEALTH EFFECTS 2.1 INTRODUCTION The primary purpose of this chapter is to provide public health officials, physicians, toxicologists, and other interested individuals and groups with an overall perspective of the toxicology of cyanide and a depiction of significant exposure levels associated with various adverse health effects. It contains descriptions and evaluations of studies and presents levels of significant exposure for cyanide based on toxicological studies and epidemiological investigations. 2.2 DISCUSSION OF HEALTH EFFECTS BY ROUTE OF EXPOSURE To help public health professionals address the needs of persons living or working near hazardous waste sites, the information in this section is organized first by route of exposure--inhalation, oral, and dermal--and then by health effect--death, systemic, immunological, neurological, developmental, reproductive, genotoxic, and carcinogenic effects. These data are discussed in terms of three exposure periods--acute (14 days or less), intermediate (15-364 days), and chronic (365 days or more). Levels of significant exposure for each route and duration are presented in tables and illustrated in figures. The points in the figures showing no-observed-adverse-effect levels (NOAELS) or lowest-observed-adverse-effect levels (LOAELS) reflect the actual doses (levels of exposure) used in the studies. LOAELSs have been classified into "less serious” or "serious" effects. These distinctions are intended to help the users of the document identify the levels of exposure at which adverse health effects start to appear. They should also help to determine whether or not the effects vary with dose and/or duration, and place into perspective the possible significance of these effects to human health. The significance of the exposure levels shown in the tables and figures may differ depending on the user’s perspective. For example, physicians concerned with the interpretation of clinical findings in exposed persons may be interested in levels of exposure associated with "serious" effects. Public health officials and project managers concerned with appropriate actions to take at hazardous waste sites may want information on levels of exposure associated with more subtle effects in humans or animals (LOAEL) or exposure levels below which no adverse effects (NOAEL) have been observed. Estimates of levels posing minimal risk to humans (Minimal Risk Levels, MRLs) may be of interest to health professionals and citizens alike. Estimates of exposure levels posing minimal risk to humans (MRLs) have been made, where data were believed reliable, for the most sensitive noncancer effect for each exposure duration. MRLs include adjustments to reflect human variability and extrapolation of data from laboratory animals to humans. Although methods have been established to derive these levels (Barnes and Dourson 1988; EPA 1989a), uncertainties are associated with these techniques. Furthermore, ATSDR acknowledges additional uncertainties inherent in the application of the procedures to derive less than lifetime MRLs. As an example, acute inhalation MRLs may not be protective for health effects that are delayed in development or are acquired following repeated acute insults, such as hypersensitivity reactions, asthma, or chronic bronchitis. As these kinds of health effects data become available and methods to assess levels of significant human exposure improve, these MRLs will be revised. This section provides information regarding known health effects of cyanide exposure. Exposure to hydrogen cyanide gas is most common by inhalation. In the discussion below, inhalation exposures are expressed as ppm hydrogen cyanide. Exposure to cyanide can also occur by the inhalation of cyanogen gas, a dimer of cyanide. However, cyanogen disproportionates in aqueous solution into CN" and OCN" ions (Cotton and Wilkinson 1980). 8 2. HEALTH EFFECTS The rate of the disproportionation depends upon the pH and is faster in basic (e.g., hydrogen cyanide is a major species in blood with a pH of 7.38-7.44) than in acidic media (e.g., hydrogen cyanide is the only species in stomach contents with a pH of 3). The amount of cyanide ion formed within a body tissue or fluid as a result of exposure to cyanogen will be kinetically controlled, and the amount may be variable in different body tissues and fluids even when a kinetic equilibrium is reached. Thus, it is difficult to express the exposure to cyanogen in body tissue or fluids in terms of cyanide. Therefore, studies regarding exposure to cyanogen are discussed in the text as ppm cyanogen, but are not included in Levels of Significant Exposure tables or figures. Oral exposure to cyanide usually results from ingestion of cyanide salts and hydrocyanic acid. Sodium cyanide and potassium cyanide are the most frequently studied cyanide compounds. Copper cyanide, potassium silver cyanide, silver cyanide, and calcium cyanide are other compounds that humans could encounter through oral or dermal exposure. Exposure to cyanide can also occur through ingestion of cyanogenic glycosides and cyanohydrin in cassava roots or fruit pits. Cassava roots form the staple diet of some populations in Africa. When possible, all oral exposures are expressed as mg CN/kg/day. 2.2.1 Inhalation Exposure 2.2.1.1 Death Due to inhibition of cellular respiration, inhalation exposure to sufficient concentrations of hydrogen cyanide gas can rapidly cause death, which has led to the use of hydrogen cyanide in gas chamber executions. An average fatal concentration for humans was estimated as 546 ppm hydrogen cyanide after a 10-minute exposure (McNamara 1976). In one case, a worker exposed to 200 ppm hydrogen cyanide in a silver plating tank became unconscious and eventually died even though he had received antidotal therapy in a hospital (Singh et al. 1989). In other cases, exposure to 270 ppm hydrogen cyanide led immediately to death, 181 ppm exposure was fatal after 10 minutes, and 135 ppm after 30 minutes in humans (Dudley et al. 1942; Singh et al. 1989). Exposure <1 hour to 110-135 ppm hydrogen cyanide can be life threatening, while exposure to 18-36 ppm for the same period of time may not cause immediate or late effects (Dudley et al. 1942). A small increase in the number of expected deaths was reported among workers exposed to sodium cyanide (unspecified concentration) over a 14-year period relative to an unexposed group (Du Pont 1971). The difference, however, was not statistically significant and the causes of death did not support an effect of cyanide. However, due to design limitations, the findings from the study (Du Pont 1971) should be regarded as inconclusive. Levels of acute exposure resulting in animal deaths were reported in numerous studies and LCs, values were provided for several species. Time to death inversely correlated with cyanide concentrations during exposure. Inhalation LC, values of hydrogen cyanide in rats ranged from 142 ppm for 60 minutes to 3,417 ppm for 10 seconds (Ballantyne 1983a; Higgins et al. 1972). Longer exposure to cyanide resulted in lower LCy, values in mice (Higgins et al. 1972; Matijak-Schaper and Alarie 1982). LCs, values for hydrogen cyanide in rabbits ranged from 208 ppm for 30 minutes to 2,200 ppm for 45 seconds (Ballantyne 1983a). In addition, LCy, values have also been calculated for cats (182 ppm) and goats (410 ppm) for 30-minute exposures (ten Berge et al. 1986). Lethal concentrations were also reported in experiments with dogs exposed for acute (Haymaker et al. 1952) and intermediate durations. Both studies used small numbers of dogs for different exposure regimens so that statistical significance could not be evaluated. The LCs, values in each species and LOAEL values for death in humans in the acute duration category are recorded in Table 2-1 and plotted in Figure 2-1. TABLE 2-1. Levels of Significant Exposure to Cyanide - Inhalation Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure Species frequency System (ppm) (ppm) (ppm) Reference Form ACUTE EXPOSURE Death 1 Human 1d 546 McNamara 1976 HCN 10 min/d 2 Human 1d 135 Dudley et al. HCN 30 min/d 1942 3 Human NS 200 Singh et al. HCN 1989 4 Rat 1d 503 (LCgq) Higgins et al. HCN 5 min/d 1972 5 Rat 1d 3,417 (LCgqg in 10 sec) Ballantyne 1983a HCN 10 sec-60 1,331 (LCgg in 1 min) min/d 387 (LCgg in 5 min) 156 (LCgg in 30 min) 142 (LCgq in 60 min) 6 Rabbit 1d 2,200 (LCgq in 45 sec) Ballantyne 1983a HCN 45 sec-30 409 (LCgg in 5 min) min/d 208 (LCgq in 35 min) 7 Mouse 1d 166 (LCgq) Mati jak-Schaper HCN 30 min/d and Alarie 1982 8 Mouse 1d 323 (LCgq) Higgins et al. HCN 5 min/d 1972 9 Cat 1d 182 (LCgq) ten Berge et al. HCN 30 min/d 1986 10 Goat 1d 410 (LCgq) ten Berge et al. HCN 30 min/d 1986 S103443 H1TV3H ¢ TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure Species frequency System (ppm) (ppm) (ppm) Reference Form Systemic 1" Human 1d Derm/oc 452 (loss of Bonsall 1984 HCN 13 min/d peripheral vision after recovery) 12 Rat 1d Cardio 200 (increased O'Flaherty and HCN 12.5 min/d creatinine Thomas 1982 phosphokinase activity) 13 Mouse 1d Resp 63 (DCgq) Mati jak-Schaper HCN 30 min/d and Alarie 1982 14 Monkey 1d Resp 100 (severe dyspnea) Purser et al. HCN 30 min/d 1984 Cardio 100 (bradycardia, arrhythmia, T-wave abnormalities) Neurological 15 Human 1d 452 (coma) Bonsall 1984 HCN 13 min/d 16 Monkey 1d 100 (semiconsciousness, Purser et al. HCN 30 min/d disrupted 1984 respiration, EEG changes) INTERMEDIATE EXPOSURE Death 17 Dog 28 d 45 (1/4 died) Valade 1952 HCN 2-day interval 30 min/d S103443 H1TV3H 2 ol TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure? Species frequency System (ppm) (ppm) (ppm) Reference Form Systemic 18 Dog 28 d Resp 45 (dyspnea) Valade 1952 HCN 2-day Gastro 45 (vomiting) interval 30 min/d Neurological 19 Dog 28 d 45 (vascular and Valade 1952 HCN 2-day cellular central interval nervous system 30 min/d lesions) CHRONIC EXPOSURE Systemic 20 Human 5-19 yr Resp 0.19 (upper respiratory Chandra et al. HCN (occup) tract irritation) 1980, 1988 Derm/Oc 0.19 (eye irritation) 21 Human (occup) Resp 15 (dyspnea) Blanc et al. HCN Cardio 15 (palpitations) 1985 Gastro 15 (nausea) Derm/oc 15 (eye irritation) Other 15 (weight loss) 22 Human 5-15 yr Resp 6.4 (dyspnea) El Ghawabi HCN (occup) Cardio 6.4 (precordial pain) et al. 1975 Gastro 6.4 (vomiting) Hemato 6.4 (increased hemoglobin and Lymphocytes) Derm/oc 6.4 (lacrimation) Other 6.4 (thyroid enlargement) S103443 H11v3H 2 I TABLE 2-1 (Continued) LOAEL (effect) Exposure Key to, duration/ NOAEL Less serious Serious figure Species frequency System (ppm) (ppm) (ppm) Reference Form Neurological 23 Human 5-15 yr 6.4 (confusion, El Ghawabi NaCN (occup) hallucination, et al. 1975 headache, dizziness, weakness) 24 Human (occup) 15 (persistent Blanc et al. HCN headaches, 1985 dizziness, paresthesia) 25 Human 5-19 yr 0.19 (delayed memory, Chandra et al. HCN (occup) visual impairment) 1980, 1988 8The number correspond to entries on Figure 2-1. Cardio = cardiovascular; d = day(s); DCgq = concentration that resulted in 50% decrease in average respiratory rate; Derm/oc = dermal/ocular; EEG = electroencephalogram; Gastro = gastrointestinal; HCN = hydrogen cyanide; Hemato = hematological; LCgo = lethal concentration, 50% kill; LOAEL = lowest-observed-adverse-effect level; min = minute(s); NaCN = sodium cyanide; NOAEL = no-observed-adverse-effect level; NS = not specified; (occup) = occupational; Resp = respiratory; sec = second(s); yr = year(s) S103443 H11V3H 2 ct FIGURE 2-1. Levels of Significant Exposure to Cyanide - Inhalation ACUTE INTERMEDIATE (<14 Days) (15-364 Days) Systemic Systemic & & & Ny & ~ ZF & 3 & & & (ppm) & & & & & & & & 10,000 pr Bs Hen 1,000 p= ms ALE [— Av As lowe ge Ci 100 p= @14k @14 @1ex @13m @17d Pied Grad @1d 10 f= 1p Key LDSOACS0 mi LOAEL for serious effects (animals) LOAEL for less serious effects (animals) LOAEL for serious effect (humans) LOAEL for less serious effect (humans) >roon RL The number next to each point corresponds to entries in Table 2-1. S103443 H1TV3H ¢ el f20012-1 FIGURE 2-1. (ppm) 10,000 1,000 10 0.1 Levels of Significant Exposure to Cyanide - Inhalation (continued) CHRONIC (2365 Days) ) Systemic @ & > 2 S 5 & & S & o> 5\ Ni J N & &° &° 8 & é $ & & <& gS ¢ & & L lL Az Az Az Aa Az A Az A= Az Az Az Az A» Ax Ax As a Key r Rat Il LDs0AC%0 m Mouse @ LOAEL for serious effects (animals) h Rabbit ( LOAEL for less serious effects (animals) d Dog A LOAEL for serious effect (humans) c Cat A LOAEL for less serious effect (humans) k Monkey o Other The number next to each point corresponds to entries in Table 2-1. S103443 H1IV3H 2 vi 15 2. HEALTH EFFECTS 2.2.1.2 Systemic Effects The highest NOAEL values and all reliable LOAEL values for each systemic effect in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. Respiratory Effects. Initially, respiration is stimulated, but later dyspnea occurs in patients admitted to a hospital after acute hydrogen cyanide exposure (Chen and Rose 1952; Peden et al. 1986; Potter 1950). The levels of exposure in these accidental poisonings were not provided. Nasal irritation was reported in volunteers exposed to 16 ppm cyanogen for 6-8 minutes (McNemey and Schrenk 1960). No effects were reported at 8 ppm cyanogen. Dyspnea was observed in workers chronically exposed to 6.4-10.4 ppm of an unspecified cyanide form evolved from sodium cyanide and copper cyanide during electroplating (El Ghawabi et al. 1975) and in workers exposed to 15 ppm hydrogen cyanide in a silver-reclaiming facility (Blanc et al. 1985). Symptoms persisted after a 10-month nonexposure period in 50% of the workers who experienced dyspnea during exposure. Other complaints included cough, sore throat, altered sense of smell, nasal congestion, epistaxis, and hemoptysis. It must be mentioned, however, that exposure to other chemicals such as cleaners and cutting oils also occurs in electroplating operations. In contrast to the findings reported by El Ghawabi et al. (1975) and Blanc et al. (1985). no adverse respiratory effects, judged by number of cases of pneumonia, bronchitis or other diseases of the respiratory system, were observed in workers exposed to sodium cyanide (unspecified concentration) over a 14-year period, but tests for pulmonary functions were not performed (Du Pont 1971). It should be noted, however, that design limitations in the Du Pont (1971) study greatly decreased the validity of the conclusions. Severe dyspnea has been observed in rats exposed to 250 ppm cyanogen for 7.5-120 minutes (McNerney and Schrenk 1960), in dogs exposed to concentrations ranging from 149 to 663 ppm hydrogen cyanide for 2-10 minutes (Haymaker et al. 1952), and in monkeys exposed to 100 ppm hydrogen cyanide for 30 minutes (Purser et al. 1984). Pulmonary edema was found in some dogs at necropsy (Haymaker et al. 1952). Sixty-three ppm hydrogen cyanide for 30-minutes exposure resulted in a 50% decrease in respiratory rate of mice due to depression of the respiratory center (Matijak-Schaper and Alarie 1982). In intermediate-duration studies, no respiratory effects were reported in rats exposed to 25 ppm cyanogen, and a decrease in total lung moisture content was the only finding in monkeys exposed to 11 ppm cyanogen for 6 months (Lewis et al. 1984). Dyspnea was found in dogs exposed to 45 ppm hydrogen cyanide for 30 minutes at 2- to 8-day intervals for 28-96 days (Valade 1952). Cardiovascular Effects. Palpitations and hypotension were the most frequently reported cardiovascular effects in patients after accidental inhalation poisoning with cyanide; however, exact exposure levels were not known (Peden et al. 1986). Workers occupationally exposed to 6.4-10.4 ppm cyanide, which evolved from sodium cyanide and copper cyanide during electroplating, complained of precordial pain (El Ghawabi et al. 1975). About 14% of workers exposed to 15 ppm hydrogen cyanide in a silver-reclaiming facility reported palpitations and 31% reported chest pain (Blanc et al. 1985). Exposure to other chemicals such as cleaners and cutting oils may have also occurred during electroplating operations. A small increase in the expected number of myocardial infarction cases was reported in workers exposed to unspecified concentrations of sodium cyanide over a period of 14 years relative to unexposed controls (Du Pont 1971), but the difference was not statistically significant. Little additional information was provided regarding other cardiovascular functions. Also, design limitations in that study (Du Pont 1971) may have rendered the results inconclusive. 16 2. HEALTH EFFECTS Bradycardia, arrhythmias, and T-wave abnormalities were observed in monkeys exposed to 100 ppm hydrogen cyanide for 30 minutes (Purser et al. 1984). Increased cardiac-specific creatinine phosphokinase activity was measured in blood samples from rats 2 hours after 12.5 minutes of exposure to 200 ppm hydrogen cyanide for 20 days at 4-day intervals (O'Flaherty and Thomas 1982). However, no treatment-related changes were found in the hearts at histopathology. In addition, no cardiovascular effects were reported in rats and monkeys exposed to 25 ppm cyanogen for 6 months (Lewis et al. 1984). Gastrointestinal Effects. Nausea or vomiting were reported in 69% of workers exposed to =15 ppm hydrogen cyanide in a silver reclaiming facility (Blanc et al. 1985). Vomiting was also reported in workers exposed to 6.4-10.4 ppm cyanide evolved from sodium cyanide and copper cyanide during electroplating (El Ghawabi et al. 1975), but exposure to other chemicals such as cleaners and cutting oils may have also contributed to the effects. The gastrointestinal effects resulting from cyanide exposure are probably provoked by the central nervous system effects and/or by irritation of the gastric mucosa in cases in which the gas is swallowed during mouth breathing. Information regarding gastrointestinal effects in animals is limited to a report of vomiting in dogs exposed to 45 ppm hydrogen cyanide for 28-96 days (Valade 1952). Hematological Effects. Increased hemoglobin and lymphocyte count were observed in workers exposed to 6.4-10.4 ppm of an unspecified cyanide form during electroplating (El Ghawabi et al. 1975). The results were significantly different from the controls. Furthermore, punctate basophilia of erythrocytes, which indicated toxic poisoning, was present in 28 of 36 subjects. It must be mentioned that exposure to copper, a known hematotoxic agent, also occurred during the electroplating operations. In animals, no hematological effects were found in rats and monkeys exposed to 25 ppm cyanogen 6 hours/day, 5 days/week for 6 months (Lewis et al. 1984). Musculoskeletal Effects. No studies were located regarding musculoskeletal effects in humans after inhalation exposure to cyanide. Convulsions and muscle rigidity were observed in dogs; each dog was acutely exposed to a different concentration of hydrogen cyanide ranging from 149 to 633 ppm hydrogen cyanide (Haymaker et al. 1952). These effects are common in acute cyanide poisonings and reflect the effects of cyanide on the central nervous system. No musculoskeletal effects were observed in rats or monkeys exposed to 25 ppm cyanogen during an intermediate- duration exposure (Lewis et al. 1984). Hepatic Effects. No studies were located regarding hepatic effects in humans after inhalation exposure to cyanide. The liver does not appear to be a target for cyanide toxicity after inhalation exposure in animals. Only one study reported on pathological and histopathological examinations. No changes were found in rats and monkeys exposed to 25 ppm cyanogen for 6 months (Lewis et al. 1984). Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to cyanide. No histopathological changes were observed in the kidneys of rats and monkeys exposed to 25 ppm cyanogen 6 hours/day, 5 days/week for 6 months (Lewis et al. 1984). 17 2. HEALTH EFFECTS Dermal/Ocular Effects. Cyanogen caused eye irritation in volunteers during acute exposure to 16 ppm (McNerney and Schrenk 1960). No effect was observed in those exposed to 8 ppm. Slight loss of peripheral vision was the only persistent finding after antidotal treatment of a man who had been exposed to 452 ppm hydrogen cyanide for 13 minutes while cleaning a chemical tank (Bonsall 1984). During chronic occupational exposure, eye irritation occurred in workers of two electroplating factories where the highest hydrogen cyanide concentrations were 0.19 ppm in the general workroom air and 0.75 ppm in the breathing zone air (Chandra et al. 1988). In other studies, cyanide caused eye irritation in 58% and rash in 42% of workers exposed to 15 ppm hydrogen cyanide (Blanc et al. 1985), and lacrimation in workers exposed to 6.4 ppm hydrogen cyanide (El Ghawabi et al. 1975). The eye irritation may not be due solely to cyanide exposure as workers may be exposed to a variety of chemicals that are irritating to the eyes. Information regarding dermal or ocular effects in animals after inhalation exposure to cyanide is limited to a report of eye irritation in rats acutely exposed to 250 ppm cyanogen (McNerney and Schrenk 1960). Other Systemic Effects. In an occupational setting, loss of appetite was reported in 58% and a weight loss (mean 5.6 kg) in 50% of workers exposed to 15 ppm hydrogen cyanide in a silver-reclaiming facility (Blanc et al. 1985). Furthermore, although within normal limits, the mean thyroid stimulating hormone (TSH) levels (all exposed workers) were significantly higher than in unexposed individuals (p<0.05). T3 levels in high exposure workers were also elevated relative to unexposed workers (p<0.01). Data for T4 were not presented, but the investigators indicated that the absence of T4 abnormalities could be accounted for by the time lapse between exposure and examination (median 10.5 months). Similarly, thyroid enlargement was present in 20 of 36 workers exposed to 6.4-10.4 ppm cyanide evolved from sodium cyanide and copper cyanide (El Ghawabi et al. 1975). Thyroid ''I uptake was significantly higher when compared with the control group. It must be mentioned that exposure to other chemicals such as cleaners and cutting oils also occurs during electroplating operations. Decreased body weight was reported in rats exposed to 25 ppm cyanogen 6 hours/day, 5 days/week for 6 months (Lewis et al. 1984). 2.2.1.3 Immunological Effects No studies were located regarding immunological effects in humans or animals after inhalation exposure to cyanide. 2.2.1.4 Neurological Effects The central nervous system is a primary target for cyanide toxicity. Acute exposure of humans to fatal levels of hydrogen cyanide causes a brief stage of central nervous system stimulation followed by depression, convulsions, coma with abolished deep reflexes and dilated pupils, and death (Bonsall 1984; Chen and Rose 1952; Peden et al. 1986; Potter 1950; Singh et al. 1989). Though clinical symptoms of cyanide poisoning are well recognized, specific dose-response data are generally not known. Acute exposure to lower concentrations can cause lightheadedness, breathlessness, dizziness, numbness, and headaches (Peden et al. 1986). Chronic exposure of humans to potassium cyanide may produce severe neurological effects such as hemiparesis and hemianopia (Sandberg 1967). However, exact exposure levels associated with these effects are not known. During chronic occupational exposure, workers exposed to 15 ppm hydrogen cyanide reported fatigue, dizziness, headaches, disturbed sleep, ringing in ears, paresthesias of extremities, and syncopes (Blanc et al. 1985). A dose- effect was demonstrated on high and low exposure jobs; however, exact cyanide concentrations in the air were not known. Neurological effects persisted in some workers even after a 10-month nonexposure period. Similar 18 2. HEALTH EFFECTS effects were observed in workers exposed to 6.4 ppm cyanide (El Ghawabi et al. 1975). Clinical symptoms involved headaches, weakness, changes in taste and smell, dizziness, disturbances of accommodation, and psychosis. In another study, chronic occupational exposure of workers to hydrogen cyanide at 0.19 ppm in workroom air and 0.75 ppm in breathing zone air resulted in headaches and dizziness in workers (Chandra et al. 1988). Furthermore, when behavioral functions were tested in this cohort, an alteration of delayed memory and/or visual impairment were found in 31.5% of workers. It must be mentioned that exposure to other chemicals such as cleaners and cutting oils also occurs during electroplating operations. The central nervous system is also a primary target for cyanide toxicity in animals. Following acute exposure, neurological effects before death included restless and panic movements, poor coordination, tremor, and lethargy in rats exposed to 250 ppm cyanogen (McNemey and Schrenk 1960). When rats were exposed to unspecified concentrations of hydrogen cyanide and kept unconscious for 20-60 minutes, lesions of various degrees developed in the brain (Hirano et al. 1967; Levine 1969; Levine and Stypulkowski 1959a, 1959b). Necrosis was found mainly in the mid-sagittal sections of the brain. Demyelination was also reported (Hirano et al. 1967, 1968). Morphological signs indicative of remyelination were reported in rats several months after cyanide intoxication (Hirano et al. 1968), but it wus apparent that this process was slow and incomplete. Acute exposure of dogs, each to a different concentration ranging from 149 to 633 ppm hydrogen cyanide, resulted in motor incoordination, muscular rigidity, and coma (Haymaker et al. 1952). Extensive necrosis in the grey matter of the neural system was observed at necropsy. Acute exposure to 100 ppm hydrogen cyanide induced semiconsciousness rapidly in monkeys (Purser et al. 1984). An increase in delta activity was observed in the electroencephalogram. Cyanide exposure levels in most acute duration studies were relatively high and usually caused death in some animals. Only transitory behavioral changes were reported in monkeys exposed to 25 ppm cyanogen for 6 months (Lewis et al. 1984). No effects were found at 11 ppm exposure. Exposure of dogs to 45 ppm for 28-96 days caused tremors, convulsions, and coma (Valade 1952). Vascular and cellular lesions were found in the central nervous system. The highest NOAEL value and all reliable LOAEL values for neurological effects in each species and duration category are recorded in Table 2-1 and plotted in Figure 2-1. No studies were located regarding the following health effects in humans or animals after inhalation exposure to cyanide: 2.2.1.5 Developmental Effects 2.2.1.6 Reproductive Effects 2.2.1.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.1.8 Cancer No studies were located regarding cancer effects in humans and animals after inhalation exposure to cyanide. 19 2. HEALTH EFFECTS 2.2.2 Oral Exposure 2.2.2.1 Death An average fatal dose of 1.52 mg/kg cyanide for humans has been calculated from case report studies of intentional or accidental poisonings (EPA 1987a). The lowest fatal oral dose reported in humans is 0.56 mg/kg cyanide (Gettler and Baine 1938). Oral LDy, values were calculated for rats as 3 mg CN'/kg/day (Ballantyne 1988) or 8 mg CN'/kg/day (Smyth et al. 1969) given as sodium cyanide. Starvation had little effect on the LD, (Ballantyne 1988). An acute LD, of 11 mg CN'/kg/day as calcium cyanide was reported in rats (Smyth et al. 1969). Acute LD, values in rabbits expressed in mg CN'/kg/day showed little variation (2.34-2.7 mg CN/kg/day) regardless of whether the source was hydrocyanic acid, sodium cyanide, or potassium cyanide (Ballantyne 1983a). High mortality occurred in rats and mice that received a single dose of 6 and 4.3 mg CN/kg/day, respectively, in the form of potassium cyanide (Ferguson 1962). Greater dilution of dosages in water resulted in higher mortality. Following intermediate duration exposure, increased mortality was observed in rats exposed to 14.5 mg CN'/kg/day as copper cyanide (Gerhart 1986) and to 2.6 mg CN'/kg/day as potassium silver cyanide (Gerhart 1987). Hemolytic anemia, which probably resulted from copper toxicity, caused death in the rats exposed to copper cyanide (Gerhart 1986). The LDy, and minimum lethal dose (LD,,) values in each species and all reliable LOAEL values for death in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.2 Systemic Effects The effects of toxic doses of cyanide in humans were described in several case reports of accidental or intentional ingestion of cyanide. However, the ingested doses were usually not known or were derived empirically based on the cyanide levels in the blood. The highest NOAEL values and all reliable LOAEL values for each systemic effect in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. Respiratory Effects. Breathing irregularities occur after cyanide poisoning through oral exposure. Stertorous, deep, and rapid breathing was reported in a man who ingested =15 mg CN'/kg as potassium cyanide in a suicide attempt (Liebowitz and Schwartz 1948). A man admitted to a hospital after ingesting an unknown amount of sodium cyanide ceased breathing (Grandas et al. 1989). Tachypnea was also reported in children who were poisoned by cyanide after ingesting apricot pits (Lasch and El Shawa 1981). The respiratory stimulation results from the direct action of cyanide on the central nervous system. Respiratory effects were also observed in animals exposed to cyanide. Labored respiration was reported in rats treated with 4.35 mg CN'/kg/day as copper cyanide by gavage for 90 days (Gerhart 1986). No effects were reported at 1.45 mg CN'/kg/day. Labored respiration occurred in rats exposed at a lower dose of 0.8 mg CN'/kg/day when administered in a form of potassium silver cyanide for 90 days (Gerhart 1987). Lung congestion and hemorrhage seen at necropsy were attributed to asphyxia rather than to a direct effect of cyanide. In contrast, no respiratory effects were reported in rats exposed to a target dose of 10.4 mg CN/kg/day as hydrogen cyanide in their feed for 2 years (Howard and Hanzal 1955). The actual dose, however, may have been considerably lower than 10.4 mg/kg/day due to evaporation of hydrogen cyanide from the food. TABLE 2-2. Levels of Significant Exposure to Cyanide - Oral Exposure LOAEL (effect) Key to duration/ NOAEL Less serious Serious figure” Species Route frequency System (mg CN /kg/day) (mg CN /kg/day) (mg CN /kg/day) Reference Form ACUTE EXPOSURE Death 1 Human 1d 0.56 (LD 0) Gettler and CN’ 1x/d Baine 1938 2 Rat (GW) 1d 6 (19/20) Ferguson 1962 KCN 1x/d 3 Rat (GW) 1d 8 (LDgq) Smyth et al. NaCN 1x/d 1969 4 Rat (GW) 1d 11 (Lbgq) Smyth et al. Ca(CN), ~ 1x/d 1969 f 5 Rat (GW) 1d 2.7 (LDgQ) Ballantyne NaCN re 1x/d 1988 - om 6 Rabbit (GW) 1d 2.39 (Lbgq) Ballantyne HCN A 1x/d 1983a Qe wn 7 Rabbit (GW) 1d 2.34 (LDgq) Ballantyne KCN 1x/d 1983a 8 Rabbit (GW) 1d 2.70 (LDgq) Ballantyne NaCN 1x/d 1983a 9 Mouse (GW) 1d 4.3 (19/20) Ferguson 1962 KCN 1x/d Systemic 10 Human 1d Resp 15 (hyperventilation) Liebowitz and KCN 1x/d Cardio 15 (shallow pulse, Schwartz 1948 inaudible heart sounds) Hemato 15 Renal 15 (albuminuria) 4 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure? Species Route frequency System (mg CN /kg/day) (mg CN /kg/day) (mg CN /kg/day) Reference Form 1" Hamster (F) Gd3-14 Other 1.1 (30% decreased Frakes et al. Cassava weight gain 1986 of dams) Neurological 12 Human 1d 15 (coma) Liebowitz and KCN 1x/d Schwartz 1948 Developmental 13 Hamster (F) Gd3-14 11.9 (decreased fetal Frakes et al. Cassava weight and delayed 1986 ossification) Reproductive 14 Hamster (F) Gd3-14 11.9 Frakes et al. Cassava 1986 INTERMEDIATE EXPOSURE Death 15 Rat (G) 90d 2.6 (9/40) Gerhart 1987 KAgCN 5 1x/d Systemic 16 Rat (G) 90d Resp 1.45 4.35 (labored Gerhart 1986 CuCN 1x/d respiration) Cardio 14.5 Derm/oc 14.5 (discolored inguinal fur) Other 1.45 4.35 (12% decrease body weight gain in males) S103443 H1V3H 2 134 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure® Species Route frequency System (mg CN /kg/day) (mg CN /kg/day) (mg CN /kg/day) Reference Form 17 Rat (F) 11.5 mo Other 30 (increased Philbrick KCN thyroid weight et al. 1979 and decreased function, 24% decrease body weight gain) 18 Rat (G) 90d Resp 0.8 (labored Gerhart 1987 KAGCN 1x/d respiration) Cardio 2.6 7.8 (increased heart weight) Gastro 7.8 Hemato 2.6 7.8 (increased hemoglobin) Hepatic 7.8 Renal 2.6 7.8 (proteinuria, increased blood urea nitrogen) Derm/oc 0.8 2.6 (ocular opacity, discolored fur) Other 0.8 2.6 (21% decrease body weight gain in males) 19 Pig (F) 110d Renal 0.64 (proliferation of Tewe and KCN Gd 1-110 glomerular cells Maner 1981b in dams) Other 5.61 11.34 (thyroid gland hypofunction in dams) 20 Pig (GW) 24 wk Gastro 0.4 0.7 (increased Jackson 1988 KCN 7d/wk vomiting) 1x/d Other 0.4 (thyroid gland hypofunction) Neurological 21 Rat (6) 90d 0.8 (hypoactivity) 7.8 (convulsions, Gerhart 1987 KAgCN 1x/d lethargy) S103443 H1V3H ¢ 44 TABLE 2-2 (Continued) LOAEL (effect) Exposure Key to duration/ NOAEL Less serious Serious figure? Species Route frequency System (mg CN /kg/day) (mg CN /kg/day) (mg CN /kg/day) Reference Form 22 Rat (F) 11.5 mo 30 (myelin Philbrick KCN degeneration in et al. 1979 spinal cord) 23 Rat (G) 90d 14.5 (lethargy) Gerhart 1986 CuCN 1x/d 24 Pig (F) 24 wk 0.4 (reduced Jackson 1988 KCN 7d/wk exploratory, 1x/d increased victimization behavior) Developmental 25 Rat (F) Gd 1-16 1.2 51 (decreased growth Tewe and KCN or 1-20 in pups) Maner 1981a Ld 1-21 Reproductive 26 Rat (G) 90d 14.5 Gerhart 1986 CuCN 1x/d 27 Rat (G) 90d 2.6 Gerhart 1987 KAgCN, 1x/d 8The number corresponds to entries on Figure 2-2. Ca(CN), = calcium cyanide; Cardio = cardiovascular; CN" = cyanide ion; CuCN = copper cyanide; d = day(s); Derm/oc = dermal /ocular; (F) = feed; (G) = gavage; Gastro = gastrointestinal; Gd = gestation day; (GW) = gavage in water; HCN = hydrogen cyanide; Hemato = hematological; KAgCN, = potassium silver cyanide; KCN = potassium cyanide; Ld = lactation day: LDgo = lethal dose, 50% kill, LD o = lowest lethal dose; LOAEL = lowest-observed-adverse-effect level; mo = month(s); NaCN = sodium cyanide; NOAEL = no-observed- adverse-effect level; Resp = respiratory; wk = week(s); yr = year(s); 1x = one time S103443 H1TV3H 2 €e FIGURE 2-2. Levels of Significant Exposure to Cyanide - Oral ACUTE (<14 Days) Systemic > AN @ Q QS 9 & & & & xO & o SS & SS & 3S oO ~C KR <> 3 & ~ A QO & & & & & ° 0d &° & (mgkg/day) g FL LLY Xr ¢ 3 100 p= Ao Ao FANT Ao A oe D13e Oras 10 p= > 2 @om h ug Lk D11s A Key r Rat I LDsoAC50 m Mouse @ LOAEL for serious effects (animals) h Rabbit ( LOAEL for less serious effects (animals) oi lk s Hamster O NOAEL (animals) } p Pig A LOAEL for serious effect (humans) A LOAEL for less serious effect (humans) /\ NOAEL (humans) The number next to each point corresponds to entries in Table 2-2. S103443 H1TV3H 2 ve f29012-3 FIGURE 2-2. Levels of Significant Exposure to Cyanide - Oral (continued) (mg/kg/day) 100 10 0.1 INTERMEDIATE (15-364 Days) Systemic o A \ « A 8 Ky & J © & SF @ 0 > & $S § .& . Ss && 0 © « C KR > Q & N & & & & S 3 3 & & > 2 & RK & & SS > 3 KR Q <& © Ns Ns x Q O <~ < Mase Mn @2 Ore Orer Dz Qsr 1op Qr Ore Qree Orr @er @2r Oror Qe Qe @ 15 O1er Oar Ore [¢ JET JT: Qe Orer Ore Qasr Oar : Orr Oter D21r 0p Q19p Op ®20p @2p Key r Rat I LD50LC50 m Mouse @ LOAEL for serious effects (animals) h Rabbit (D LOAEL for less serious effects (animals) s Hamster O NOAEL (animals) Pp Pig A LOAEL for serious effect (humans) A LOAEL for less serious effect (humans) /\ NOAEL (humans) The number next to each point corresponds to entries in Table 2-2. S103443 H1TV3H 2 Se f2g012-4 26 2. HEALTH EFFECTS Cardiovascular Effects. Several case studies reported cardiovascular effects in humans after oral exposure to cyanide. Weak and shallow pulse and inaudible heart sounds were observed in a comatose man on hospital admission after ingestion of =15 mg CN'/kg as potassium cyanide (Licbowitz and Schwartz 1948). Following unspecific treatment with gastric lavage and glucose infusion, the pulse rate and blood pressure became elevated. Apical systolic murmur was present. No cardiovascular effects were reported during the recovery. Children poisoned by apricot pits had hypotension upon admission to a hospital (Lasch and El Shawa 1981). After intermediate and chronic duration oral exposure, cardiovascular effects in animals, if any, are minimal. Increased heart weight without any histopathological changes was observed in rats exposed to 7.8 mg CN /kg/day as potassium silver cyanide for 90 days (Gerhart 1987). No such effect was found at the 2.6 mg CN/kg/day exposure level. No cardiovascular effects were reported in rats exposed to 14.5 mg CN/kg/day as copper cyanide for 90 days (Gerhart 1986). Furthermore, no cardiovascular effects were observed in rats exposed to an estimated dose of 10.4 mg CN'/kg/day as hydrogen cyanide in their feed for 2 years (Howard and Hanzal 1955). The actual dose, however, may have been different than 10.4 mg/kg/day due to evaporation of hydrogen cyanide from the food. Gastrointestinal Effects. Solutions of sodium and potassium cyanide are alkaline and as such, can cause corrosive responses in the stomach following ingestion. The severity of gastrointestinal effects in humans after oral exposure varied in individual cases. Vomiting was reported in children poisoned by apricot pits (Lasch and El Shawa 1981). Gastrointestinal spasms were reported in a man who accidentally ingested (and inhaled) an unknown amount of potassium cyanide (Thomas and Brooks 1970). Gastric surgery for extensive necrosis had to be performed in a man after he ingested an unknown amount of sodium cyanide (Grandas et al. 1989). Diarrhea was observed in rats treated with 14.5 mg CN'/kg/day copper cyanide for an intermediate-duration level of exposure (Gerhart 1986). No effects were observed at 4.35 mg/kg/day. The diarrhea may have been due to the toxicity of copper. No gastrointestinal effects were found in rats exposed to 7.8 mg CN/kg/day as potassium silver cyanide for 90 days (Gerhart 1987). However, increased vomiting was reported in pigs in a dose as low as 0.7 mg CN'/kg/day given as potassium cyanide for 24 weeks by gavage (Jackson 1988). Chronic intestinal inflammation occurred in dogs exposed to 20.27 mg CN'/kg/day for 14.5 months (Hertting et al. 1960). Hematological Effects. Information regarding hematological effects in humans after oral exposure to cyanide is limited. No effects were reported in a man acutely exposed to 15 mg CN/kg as potassium cyanide (Liebowitz and Schwartz 1948). In animals, hematological effects were observed in studies with copper cyanide and potassium silver cyanide. Hemolytic anemia was diagnosed in the group of rats treated by gavage for 90 days with 14.5 mg CN7/kg/day as copper cyanide (Gerhart 1986). Decreased erythrocytes were reported together with decreased hemoglobin concentrations and decreased hematocrit. The diagnosis of anemia was supported by microscopic findings of pigmentation of the spleen and liver, presence of hemoglobin in the cytoplasm of the renal convoluted tubule epithelium, and by hyperplasia of hematopoietic tissue (spleen and bone marrow). Decreased hemoglobin was observed also at 4.35 mg CN'/kg/day. Hemolytic anemia is characteristic of copper toxicity; therefore, the hematological effects can be attributed to copper toxicity rather than to cyanide toxicity. Increased mean corpuscular volume, mean corpuscular hemoglobin concentration, and spleen weight indicated hematological effects in rats exposed to 7.8 mg CN'/kg/day as potassium silver cyanide for 90 days by gavage (Gerhart 1987). No effects were found at 2.6 mg CN/kg/day. The contribution of silver to the hematological effects is not known. In contrast, no hematological effects were observed in rats exposed to an estimated dose of 10.4 mg/kg/day cyanide as hydrogen cyanide in their feed for 2 years (Howard and Hanzal 1955). The actual dose, however, may have been different than 10.4 mg/kg/day due to evaporation of hydrogen cyanide from the food. Chronic 27 2. HEALTH EFFECTS exposure of dogs to sodium cyanide in capsules caused increased erythropoiesis (Hertting et al. 1960). The results are limited because only one animal was used per exposure group. Musculoskeletal Effects. Muscular rigidity was observed in humans after cyanide poisoning (Grandas et al. 1989). In Africa, spastic paralysis of both legs has been associated with cassava ingestion (Rosling et al. 1988). The effects may be related to cyanide neurotoxicity (Section 2.2.2.4). No studies were located regarding musculoskeletal effects in animals after oral exposure to cyanide. Hepatic Effects. No studies were located regarding hepatic effects in humans after oral exposure to cyanide. In animals, hepatotoxicity was observed only in a study of copper cyanide. Male rats treated for 90 days by gavage with 14.5 mg CN/kg/day as copper cyanide had increased levels of serum glutamic oxaloacetic transaminase (SGOT) and serum glutamic pyruvic transaminase (SGPT) levels, increased bilirubin and alkaline phosphatase, and decreased globulin levels in the blood (Gerhart 1986). Liver necrosis was observed in females in 4.35 mg CN/kg/day cyanide treated group. However, blood chemistry did not reveal any changes. The hepatic effects of copper cyanide are probably due to the toxicity of copper rather than of cyanide. No hepatic effects were reported in rats exposed by gavage to 7.8 mg CN7/kg/day as potassium silver cyanide for an intermediate-duration level of exposure (Gerhart 1987) or in rats exposed to an estimated dose of 10.4 mg CN'/kg/day as hydrogen cyanide in their feed for 2 years (Howard and Hanzal 1955). The actual dose, however, may have been different than 10.4 mg/kg/day due to evaporation of hydrogen cyanide from the food. Renal Effects. Information regarding renal effects of cyanide in humans is limited to one report. Albuminuria was found in a man during the first 2 days after ingestion of 15 mg CN'/kg as potassium cyanide in a suicide attempt (Liebowitz and Schwartz 1948). In animals, decreased kidney weight was observed in rats treated with 14.5 mg CN'/kg/day as copper cyanide for 90 days (Gerhart 1986). No changes were reported at 4.35 mg/kg/day exposure. Copper toxicity could have contributed to the development of kidney effects. Increased blood urea nitrogen was found at 7.8 mg CN'/kg/day, but not at 2.6 mg CN/kg/day, as potassium silver cyanide (Gerhart 1987). The contribution of silver to this effect is not known. No significant changes indicating renal effects were found at terminal bleed. Histopathologically, a proliferation of the glomerular cells in the kidney was observed in pigs exposed to 0.64 mg CN/kg/day in cassava feed for 110 days (Tewe and Maner 1981b). However, no renal effects were observed in rats exposed to an estimated dose of 104 mg CN7/kg/day as hydrogen cyanide in their feed for 2 years (Howard and Hanzal 1955); in this study, however, the actual dose may have been different due to evaporation of hydrogen cyanide from the food. Cloudy swelling of epithelial cells of renal tubules was reported in three dogs; each dog was exposed to a different dose of sodium cyanide for 14.5 months (Hertting et al. 1960). Dermal/Ocular Effects. No studies were located regarding dermal/ocular effects in humans after oral exposure to cyanide. During intermediate-duration exposure, discolored inguinal fur was found in rats exposed to 14.5 mg CN'/kg/day as copper cyanide (Gerhart 1986) and to 2.6 mg CN'/kg/day as potassium silver cyanide (Gerhart 1987). Ocular opacity was also recorded in this exposure group. No pathological findings were observed during ophthalmological examination of rats exposed to 14.5 mg CN'/kg/day as copper cyanide (Gerhart 1986). Other Systemic Effects. Cyanide naturally occurs in several plants, such as cassava, soybeans, spinach, and bamboo shoots, in which it is generated from cyanogenic glycosides. Chronic oral exposure to cyanide in humans who use cassava roots as a main source of their diet has been associated with thyroid effects. The effects are 28 2. HEALTH EFFECTS probably caused by thiocyanate, a metabolite of cyanide. The incidence of endemic goiter correlated with a cassava rich diet in the Congo (Delange and Ermans 1971). Thyroid uptake of radioiodine was decreased in the goitrous area, compared with the controls. Similarly, decreased FT4I and increased FT3I levels, T3/T4 ratio, and TSH were measured in a cohort from a village where an epidemic of spastic paraparesis was found (Cliff et al. 1986). Examined individuals also had increased thiocyanate levels in serum and urine. Thyroid effects were also found in animals exposed to cyanide. Rats that were fed a diet containing 30 mg CN/kg/day as potassium cyanide for 4 months had a significant decrease in plasma thyroxine levels and thyroxine secretion rates; at 11 months, treated rats continued to show a significant decrease in thyroxine secretion rates, but plasma thyroxine concentrations were at normal levels (Philbrick et al. 1979). A significant increase in relative thyroid weight was also recorded at 11 months in the treated rats. When pigs were fed a diet containing potassium cyanide and/or cassava roots during pregnancy, an increase in the maternal thyroid weight and thyroid gland hypofunction were observed in 11.34 mg CN/kg/day exposure group (Tewe and Maner 1981b). No effects on thyroid gland were found at 5.61 mg CN'/kg/day. However, thyroid effects have been reported at even lower doses in another study. Decreased thyroid function was found in pigs exposed to 0.4 mg CN/kg/day as potassium cyanide for 24 weeks by gavage (Jackson 1988). Decreased body weight gain was cited as one of the effects of exposure to copper cyanide and potassium silver cyanide. The effect was reported in male rats exposed to 4.35 mg CN/kg/day as copper cyanide, but not in those exposed to 1.45 mg CN'/kg/day (Gerhart 1986). Furthermore, decreased weight gain was found in male rats exposed to 2.6 mg CN'/kg/day as potassium silver cyanide (Gerhart 1987). The presence of the copper or silver may have contributed to the observed decreased body weight. Female hamsters exposed to 1.1 mg CN/kg/day in cassava during pregnancy had decreased body weight gain (Frakes et al. 1986). 2.2.2.3 Immunological Effects No studies were located regarding immunological effects in humans and animals after oral exposure to cyanide. 2.2.2.4 Neurological Effects Neurological effects of cyanide poisoning in humans probably correlate with the amount ingested; however, the exact doses consumed by the victims are usually not known. Tremor was reported in a patient who accidentally ingested an unknown amount of fluid containing 2.3% silver cyanide and 6.9% sodium cyanide (Chen and Rose 1952). Children who ingested apricot pits experienced various neurological effects ranging in severity from headaches to coma (Lasch and El Shawa 1981). The severity of effects corresponded with the amount of ingested pits. Comatose patients were admitted to a hospital after ingesting 15 mg CN/kg as potassium cyanide (Liebowitz and Schwartz 1948) or an unknown amount of potassium cyanide (Thomas and Brooks 1970). Four reports were located regarding the development of parkinsonism in patients after cyanide ingestion. A woman in a light coma had positive Babinski’s sign on the right with slight right hemiparesis and dysphonia within 2 weeks after cyanide poisoning (Carella et al. 1988). Within 5 years, progressive parkinsonism, dystonia, and apraxia of the right eye opening was present. Atrophy of the cerebellum and distinct ventricular enlargement in the cerebral hemispheres were revealed by computed tomography and magnetic resonance image examinations. In another case, a man went into a coma after ingesting an unknown amount of sodium cyanide (Grandas et al. 1989). Later on he regained consciousness, but was apathetic with reduced speech and a loss of balance; dystonia and severe parkinsonism developed during following years. Computed tomography scan revealed bilateral luciencies in the putamen and external globus pallidus. Severe parkinsonism also developed in two men who ingested =5.57 mg CN'/kg (Uitti et al. 1985) and 8.57 mg CN'/kg (Rosenberg et al. 1989), respectively, as potassium cyanide in suicide attempts. Lesions were reported in the globus pallidus and putamen in both cases. 29 2. HEALTH EFFECTS The effects of chronic oral exposure of humans to cyanide were studied in regions of Africa with populations that consume a high level of cassava roots (Howlett et al. 1990; Ministry of Health, Mozambique 1984; Monekosso and Wilson 1966; Money 1958; Osuntokun 1968, 1972; Osuntokun et al. 1969). A variety of neuropathies was observed in the regions. Neurological findings correlated with increased thiocyanate levels in the blood. Symmetrical hyperreflexia of the upper limbs, symmetrical spastic paraparesis of the lower limbs, spastic dysarthria, diminished visual acuity, peripheral neuropathy, cerebellar signs, and deafness were among the clinical findings (Ministry of Health, Mozambique 1984). Similar observations were made by other authors. Decreased plasma vitamin B,, levels were also detected in affected individuals (Monekosso and Wilson 1966). The central nervous system is also a primary target of orally administered cyanide in animals. Tremors, convulsions, recumbency, and lethargy were observed in rats exposed to 7.8 mg CN'/kg/day as potassium silver cyanide for 90 days by gavage (Gerhart 1987). Since of 28 of 40 rats died at this dose level, some of the effects described may represent nonspecific signs that precede death. Hypoactivity was observed in all exposed groups starting at a dose of 0.8 mg CN/kg/day. Similarly, hypoactivity was reported in rats exposed to >0.14 mg CN/kg/day as copper cyanide for 90 days by gavage (Gerhart 1986). However, silver and/or copper toxicity may have contributed to observed effects. The severity of effects increased as the dose increased. At 4.35 mg CN/kg/day, fixed posture occurred, while pronounced lethargy was noted at 14.5 mg CN'/kg/day. Decreased brain weight was reported at 14.5 mg CN'/kg/day cyanide. However, no histopathological changes were observed in the central nervous system in these studies (Gerhart 1986, 1987). Males seemed to be more sensitive to cyanide toxicity than females. Rats that were fed a diet containing 30 mg CN'/kg/day as potassium cyanide for 11.5 months had myelin degeneration in the spinal cord (Philbrick et al. 1979). In a behavioral study, cyanide exposure lead to increasing uncertainty and slower reaction response time to various stimuli, reduced exploratory behavior, and increased victimization behavior in pigs exposed to 0.4 mg CN7/kg/day as potassium cyanide for 24 weeks (Jackson 1988). In contrast, no neurological effects were reported in rats exposed to an estimated dose of 10.4 mg CN/kg/day as hydrogen cyanide in their feed for 2 years (Howard and Hanzal 1955). The actual dose, however, may have been considerably lower than 10.4 mg/kg/day due to evaporation of hydrogen cyanide from the food. Degenerative changes in ganglion cells were reported in three dogs that were each exposed to a different dose ranging from 0.27 to 1.68 mg CN'/kg/day as sodium cyanide in capsules for 14.5 months (Hertting et al. 1960). The highest NOAEL value and all reliable LOAEL values for neurological effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.5 Developmental Effects No studies were located regarding developmental effects in humans after oral exposure to cyanide. Developmental abnormalities (microcephaly with open eyes, limb defects, and growth retardation) were observed in 28% of the fetuses of rats exposed to feed containing 80% cassava powder during gestation (Singh 1981). Teratogenic effects (encephalocele and rib abnormalities) were reported in hamsters exposed to a single oral dose of amygdalin during gestation (Willhite 1982). The doses of cyanide could not be determined from these studies. Fetotoxicity (reduced fetal weight and ossification) were found in the offspring of hamsters exposed to a cassava diet providing 11.9 mg CN/kg/day during pregnancy (Frakes et al. 1986). In contrast, no major developmental effects were observed in rats that were fed a basal cassava diet providing =1.2 mg CN7/kg/day or in rats whose cassava feed was supplemented with potassium cyanide bringing the total dose to 51 mg CN'/kg/day (Tewe and Maner 1981a). The rats were exposed to cyanide during gestation days 16-20 and then for 21 days during lactation. When their offspring were exposed to similar diets providing doses of =1.2 and 51 mg CN'/kg/day, decreased growth was observed in the higher dosed weanlings regardless of the exposure in utero. When pigs 30 2. HEALTH EFFECTS were fed a cassava diet alone or one supplemented with potassium cyanide for 110 gestation days, no effects on number of fetuses or fetal weight were observed in the 11.34 mg CN'/kg/day cyanide exposed group (Tewe and Maner 19810). The highest NOAEL value and all reliable LOAEL values for developmental effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.6 Reproductive Effects No studies were located regarding reproductive effects in humans after oral exposure to cyanide. Increased resorptions were reported in rats fed a diet containing 80% cassava powder during gestation (Singh 1981). No reproductive effects were found in a group fed with 50% cassava powder. Furthermore, no changes were observed in the number of implantations and resorptions in hamsters exposed to cyanide in a cassava diet that provided 11.9 mg CN'/kg/day (Frakes et al. 1986). Increased gonadal weight was observed in male rats exposed to 14.5 mg CN'kg/day as copper cyanide (Gerhart 1986) or 2.6 mg CN'/kg/day as potassium silver cyanide (Gerhart 1987); however, no histological lesions were found. No effects were observed in female rats in either study. The highest NOAEL values for reproductive effects in each species and duration category are recorded in Table 2-2 and plotted in Figure 2-2. 2.2.2.7 Genotoxic Effects No studies were located regarding genotoxic effects in humans after oral exposure to cyanide. A single oral dose of 1 mg CN'/kg cyanide as potassium cyanide did not cause an inhibition of testicular deoxyribonucleic acid (DNA)-synthesis in mice (Friedman and Staub 1976). Other genotoxicity studies are discussed in Section 2.4. 2.2.2.8 Cancer No studies were located regarding cancer effects in humans and animals after oral exposure to cyanide. 2.2.3 Dermal Exposure Chronic dermal exposure of humans to cyanide can occur in occupational settings. However, the main route of exposure is considered to be inhalation and, therefore, the occupational exposure studies are discussed in Section 2.2.1. 2.2.3.1 Death An average fatal dose for dermal exposure of 100 mg CN/kg as hydrogen cyanide was estimated for humans (Rieders 1971). However, no details were provided. LDy, values were calculated for dermal exposure to cyanide in rabbits (Ballantyne 1983a). The LD, was 6.75 mg CN/kg when cyanide was applied as hydrogen cyanide, 7.74 mg CN/kg as sodium cyanide, and 31 2. HEALTH EFFECTS 8.93 mg CN'/kg as potassium cyanide. Moistening the skin slightly lowered, and abrading the skin substantially lowered, the dermal LD, of cyanide as sodium cyanide (Ballantyne 1988). Similar differences in toxicity of various chemical forms of cyanide were observed after cyanide was applied to the inferior conjunctival sac of one eye (Ballantyne 1983a, 1983b; 1988). Transocular LD, values were 1.0 mg CN'/kg as hydrogen cyanide, 2.4 mg CN'/kg as sodium cyanide, and 3.15 mg CN/kg as potassium cyanide. The death occurred within 3-12 minutes. Deaths occurred also in guinea pigs when their skin was exposed to hydrogen cyanide (Fairley et al. 1934: Walton and Witherspoon 1926). However, the doses could not be quantified. 2.2.3.2 Systemic Effects The effects of dermal exposure to cyanide in humans and animals are reported below. No studies were located regarding hematological, musculoskeletal, or hepatic effects in humans or animals after dermal exposure to cyanide. Respiratory Effects. Breathing irregularities including Cheyne-Stokes respiration developed in persons who fell into cisterns containing copper cyanide, silver cyanide, or potassium cyanide (Dodds and McKnight 1985; Trapp 1970) or whose hands were exposed to hydrogen cyanide (Potter 1950). The effects reflected the central nervous system toxicity of cyanide. Rapid breathing was reported as the first sign of toxicity in rabbits that received 0.90 mg CN'kg as hydrogen cyanide, 1.67 mg CN'/kg as sodium cyanide, and 2.52 mg CN'/kg as potassium cyanide in their conjunctival sacs (Ballantyne 1988). Similarly, labored breathing preceded coma and death in guinea pigs exposed dermally to unknown doses of hydrogen cyanide (Fairley et al. 1934; Walton and Witherspoon 1926). These LOAEL values are recorded in Table 2-3. Cardiovascular Effects. Peripheral vasoconstriction and gross plasma extravasation were reported in a man who accidentally fell into a cistern with hot copper cyanide (Dodds and McKnight 1985). Palpitations were recorded in men who wore respiratory masks while working in an atmosphere containing 20,000 ppm hydrogen cyanide for 8-10 minutes (Drinker 1932). The masks were reported to give excellent respiratory protection. Furthermore, at the time of this report, the Bureau of Mines had required that canisters approved for use against hydrogen cyanide carry a label stating that the canisters will protect against inhalation exposure to hydrogen cyanide concentrations of 20,000 ppm, but that exposure to such high concentrations is not safe because the gas is absorbed through the unprotected skin. Therefore, the effects seen in these men may have been due to dermal exposure. The exposure level of 20,000 ppm is recorded in Table 2-3. No studies were located regarding cardiovascular effects in animals after dermal exposure to cyanide. Gastrointestinal Effects. No studies were located regarding gastrointestinal effects in humans after dermal exposure to cyanide. Acute dermal exposure of guinea pigs to an unknown concentration of hydrogen cyanide resulted in submucous hemorrhages in the stomach as observed at histopathology (Fairley et al. 1934). Renal Effects. The information regarding renal effects following dermal exposure to cyanide in humans is limited to one case report. Transitory oliguria (scanty urination) was observed in a patient who accidentally fell into a cistern containing 1,000 gallons of hot copper cyanide and remained there for 3 minutes before being rescued (Dodds and McKnight 1985). TABLE 2-3. Levels of Significant Exposure to Cyanide - Dermal LOAEL (effect) Exposure duration/ A Less serious Serious Species frequency System (mg CN /kg/day)? (mg CN /kg/day)? (mg CN /ka/day)? Reference Form ACUTE EXPOSURE Death Rabbit 1d 8.93 (dermal LDgq) Ballantyne KCN 1x/d 1983a Rabbit 1d 3.15 (transocular LDgq) Ballantyne KCN 1x/d 1983a, 1983b Rabbit 1d 1.0 (transocular LDgn) Ballantyne HCN 1x/d 1983a, 1983b Rabbit 1d 6.75 (dermal LDgq) Ballantyne HCN 1x/d 1983a Rabbit 1d 4.08 (dermal LDgq - Ballantyne NaCN 1x/d abraded skin) 1988 Rabbit 1d 6.25 (dermal LDgq - Ballantyne NaCN 1x/d moist skin) 1988 Rabbi t 1d 2.4 (transocular LDgn) Ballantyne NaCN 1x/d 1988 Rabbit 1d 7.74 (dermal LDgq) Ballantyne NaCN 1x/d 1983a Systemic Human 1d Cardio 20,000 ppm (palpitations) Drinker 1932 HCN 8-10 min/d Rabbit 1d Resp 2.52 (rapid breathing) Ballantyne KCN 1x/d Derm/oc 2.52 (corneal opacity, 1983b keratitis) S103443 HLV3H 2 ce TABLE 2-3 (Continued) LOAEL (effect) Exposure duration/ NOAEL a Less serious Serious Species frequency System (mg CN /kg/day) (mg CN /kg/day)? (mg CN /kg/day)? Reference Form Rabbit 1d Resp 0.90 (rapid breathing) Ballantyne HCN 1x/d Derm/oc 0.90 (corneal opacity, 1983b keratitis) Rabbit 1d Resp 1.67 (rapid breathing) Ballantyne NaCN 1x/d Derm/oc 1.67 (corneal opacity, 1983b, 1988 keratitis) Neurological Human 1d 20,000 ppm (dizziness) Drinker 1932 HCN 8-10 min/d Rabbit 1d 1.67 (coma) Ballantyne NaCN 1x/d 1983b, 1988 Rabbit 1d 0.90 (coma) Ballantyne HCN 1x/d 1983b Rabbit 1d 2.52 (coma) Ballantyne KCN 1x/d 1983b S103443 HL1TV3H 2 151 3all units in mg CN'/kg/d, unless otherwise specified. Cardio = cardiovascular; CN" = cyanide ion; d = day(s); Derm/oc = dermal/ocular; HCN = hydrogen cyanide; KCN = potassium cyanide; LDgq = lethal dose, 50% kill; LOAEL = lowest-observed-adverse-effect level; min = minute(s); NaCN = sodium cyanide; NOAEL = no-observed- adverse-effect level; Resp = respiratory; 1x = one time 34 2. HEALTH EFFECTS No studies were located regarding renal effects in animals after dermal exposure to cyanide. Dermal/Ocular Effects. No studies were located regarding dermal/ocular effects in humans after dermal exposure to cyanide. When the skin of rabbits was exposed to 500 ppm cyanide as cyanogen for 8 hours, no dermal lesions were found (McNerney and Schrenk 1960). Vascular congestion was reported in the skin of guinea pigs after exposure to unknown doses of hydrogen cyanide for 65 minutes (Fairley et al. 1934). Cyanide toxicity was tested in rabbits by applying it to the inferior conjunctival sac of one eye (Ballantyne 1983b, 1988). Irritation, lacrimation, and conjunctival hyperemia were present immediately after the treatment. Keratitis developed in some rabbits after a cyanide application of 0.90 mg CN/kg as hydrogen cyanide, 1.67 mg CN/kg as sodium cyanide, and 2.52 mg CN'/kg as potassium cyanide. These LOAEL values are recorded in Table 2-3. 2.2.3.3 Immunological Effects No studies were located regarding immunological effects in humans and animals after dermal exposure to cyanide. 2.2.3.4 Neurological Effects Deep coma developed in persons who accidentally fell into cisterns containing copper cyanide (Dodds and McKnight 1985), silver cyanide, and potassium cyanide (Trapp 1970). Similarly, a worker, whose hand was exposed to liquid hydrogen cyanide, fell into a coma, lost deep reflexes, and showed dilated pupils within 5 minutes (Potter 1950). Men working in an atmosphere containing 20,000 ppm hydrogen cyanide for 8-10 minutes experienced dizziness, weakness, and palpitations (Drinker 1932). The workers wore masks that were reported to give excellent respiratory protection. Furthermore, at the time of this report, the Bureau of Mines had required that canisters approved for use against hydrogen cyanide carry a label stating that the canisters will protect against inhalation exposure to hydrogen cyanide concentrations of 20,000 ppm, but that exposure to such high concentrations is not safe because the gas is absorbed through the unprotected skin. Therefore, the effects seen in these men were probably due to dermal exposure. Weak and ataxic movements, convulsions, and coma developed in rabbits that received 0.90 mg CN/kg as hydrogen cyanide, 1.67 mg CN'/kg as sodium cyanide, and 2.52 mg CN/kg as potassium cyanide into their conjunctival sacs (Ballantyne 1983b, 1988). Similarly, convulsions and coma preceded death in guinea pigs exposed dermally to unknown doses of hydrogen cyanide (Fairley et al. 1934; Walton and Witherspoon 1926). No studies were located regarding the following health effects in humans or animals after dermal exposure to cyanide: 2.2.3.5 Developmental Effects 2.2.3.6 Reproductive Effects 2.2.3.7 Genotoxic Effects Genotoxicity studies are discussed in Section 2.4. 2.2.3.8 Cancer No studies were located regarding cancer in humans or animals after dermal exposure to cyanide. 35 2. HEALTH EFFECTS 2.3 TOXICOKINETICS 2.3.1 Absorption 2.3.1.1 Inhalation Exposure Cyanide is rapidly absorbed following inhalation exposure. It has been reported that hydrogen cyanide at concentrations >2,000 ppm is fatal to humans in <1 minute (Rieders 1971). Humans retained 58-77% of hydrogen cyanide in the lungs after inhaling the gas through normal mouth breathing (Landahl and Herrmann 1950). Quantitative data on the absorption of hydrogen cyanide by inhalation were reported in dogs (Gettler and Baine 1938). During exposure to an unknown concentration of hydrogen cyanide, one dog reportedly absorbed 16.0 mg (1.55 mg/kg); the other dog absorbed 10.1 mg (1.11 mg/kg). More recent quantitative data were not available. 2.3.1.2 Oral Exposure Absorption of cyanide across the gastrointestinal mucosa depends on the pH of the gut and the pKa and lipid solubility of the cyanide compound. Hydrogen cyanide is a weak acid with a pKa of 9.2 at a temperature of =25°C. The acidic environment in the stomach favors the non-ionized form of hydrogen cyanide and facilitates absorption. Information regarding the rapid lethal effects following oral intake of cyanides in humans (Gosselin et al. 1976) indicates that cyanides are rapidly absorbed from the gastrointestinal tract. In a case study, an 80 kg male ingested an estimated 15-25 mg CN'/kg as potassium cyanide in a suicide attempt (Liebowitz and Schwartz 1948). Based on a concentration of 220 mg hydrogen cyanide/L in the blood 2 hours after ingestion, it was estimated that the patient had 1.2 g hydrogen cyanide in the blood, with =2.3 g CN" in the body. When three dogs were given a potassium cyanide solution by gavage, the amount of cyanide absorbed was determined by the difference between the amount of cyanide given and the amount of cyanide left in the stomach and intestines (Gettler and Baine 1938). Dogs treated with 8, 20, and 40 mg CN/kg as potassium cyanide absorbed 5.76, 4.8, and 6.64 mg cyanide/kg (72, 24, and 17%), respectively. Rats excreted 47% of a dose of radioactivity in the urine during 24 hours following gavage treatment with 2 mg CN/kg as radiolabeled potassium cyanide (Farooqui and Ahmed 1982), indicating that at least 47% of the cyanide was absorbed in 24 hours. 2.3.1.3 Dermal Exposure No studies were located regarding absorption in humans after dermal exposure to cyanides. Hydrogen cyanide is moderately lipid-soluble, which, along with its small size, allows it to rapidly penetrate the epidermis. In addition, some cyanide compounds, such as potassium cyanide, have a corrosive effect on the skin that increases the rate of absorption (NIOSH 1976). Evidence that cyanide can be absorbed through the skin of humans is provided in case reports of toxic effects in humans after accidental dermal contact with cyanide (see Section 2.2.3). Information regarding dermal absorption of cyanide in animals was provided in studies of guinea pigs and dogs (Walton and Witherspoon 1926). When a small area of the shaved abdomen of guinea pigs was exposed to hydrogen cyanide vapor, the signs of cyanide toxicity observed included rapid respiration followed by general twitching of muscles, convulsions, and death. In a similar experiment, shaved and unshaved dogs were placed in a chamber in which their bodies, with the exception of the head and neck, were exposed to hydrogen cyanide vapor. No signs of toxicity were reported after exposure to 5,000 ppm hydrogen cyanide for 180 minutes. 36 2. HEALTH EFFECTS Deaths occurred after exposure to 13,400 ppm hydrogen cyanide for 47 minutes and suggested dermal absorption. Further indirect evidence regarding dermal absorption of cyanide as hydrogen cyanide or its salts (Ballantyne 1983a, 1983b, 1988) can be found in Section 2.2.3. 2.3.2 Distribution 2.3.2.1 Inhalation Exposure Once cyanide is absorbed, it is rapidly distributed by the blood throughout the body. Tissue levels of hydrogen cyanide were 0.75, 0.42, 0.41, 0.33, and 0.32 mg/100 g of tissue in the lung, heart, blood, kidney, and brain, respectively, in a man who died following inhalation exposure to hydrogen cyanide gas (Gettler and Baine 1938). In another case, tissue cyanide levels from a man who died from inhalation of hydrogen cyanide were reported as 0.5 mg per 100 mL of blood and 0.11, 0.7, and 0.3 mg/100 g in the kidney, brain, and liver, respectively (Finck 1969). Urine cyanide levels were reported as 0.2 mg/100 mL, and 0.03 mg/100 g was found in the gastric contents. Following chronic occupational exposure to 0.19-0.72 ppm hydrogen cyanide, 56.0 and 18.3 pg CN'/mL was found in the blood of smokers and nonsmokers, respectively (Chandra et al. 1980). The cyanide levels in control groups were 4.8 pg/mL for smokers and 3.2 pg/mL for nonsmokers. In two dogs exposed to unspecified fatal concentrations of hydrogen cyanide, the highest cyanide levels were found in the lungs, blood, and heart (Gettler and Baine 1938). Rats exposed to hydrogen cyanide gas at 356 or 1,180 ppm died within <10 and 5 minutes, respectively (Yamamoto et al. 1982). Samples taken immediately after respiration stopped showed that the pattern of tissue distribution of cyanide did not vary with the concentration used. In averaging data for both dose groups, tissue concentrations, reported as pg/g wet weight, were 4.4 in the lungs, 3.0 in the blood, 2.2 in the liver, 1.45 in the brain, and 0.68 in the spleen. Rabbits exposed to hydrogen cyanide at 2714 ppm for 5 minutes had blood and serum cyanide levels of 170 and 40 pg/dL, and tissue levels, in units of pg/100 g, of 0 in the liver, 6 in the kidney, 50 in the brain, 62 in the heart, 54 in the lung, and 6 in the spleen (Ballantyne 1983a). 2.3.2.2 Oral Exposure Small but significant levels of cyanide are present in normal, healthy human organs at concentrations of <0.5 mg CN'/kg (Feldstein and Klendshaj 1954). This cyanide includes vitamin B,,, with the source of cyanide attributed to breakdown of cyanogenic foods by bacteriological action and tobacco smoke. Cyanide levels in a woman who died 30 minutes after ingesting =1,325 mg cyanide as sodium cyanide were, in mg %: stomach contents, 3.2; brain, 0.7; urine, 0.5; blood, 0.4; kidney, 0.2; stomach wall, 0.2; and liver, 0.1 (Ansell and Lewis 1970). The mean organ levels of cyanide ion in cases of fatal poisoning were, in mg%: stomach contents, 160 (49 cases); spleen, 3.77 (22 cases); blood, 2.39 (58 cases); liver, 1.62 (48 cases); brain, 1.2 (34 cases); kidney, 0.61 (34 cases); and urine, 0.08 (17 cases) (Ansell and Lewis 1990). Brain cyanide levels ranged from 0.06 to 1.37 mg hydrogen cyanide/100 g of tissue in four humans who ingested fatal doses of cyanide (Gettler and Baine 1938). Cyanide levels in the livers of these humans ranged from 0.22 to 0.91 mg hydrogen cyanide/100 g of tissue. Cyanide levels were highest in the lungs and blood in two cases in which men died from ingestion of unknown quantities of unspecified cyanide salts (Finck 1969). Combined data from rats that died 3.3 and 10.3 minutes after gavage doses of 21 or 7 mg CN/kg as sodium cyanide showed tissue concentrations of cyanide in pg/g wet weight of: liver, 8.8; lung, 5.85; blood, 4.9; spleen, 2.1; and brain, 1.5 (Yamamoto et al. 1982). When rats were treated with 4 mg CN/kg as potassium cyanide, signs of central nervous system toxicity were observed (Ahmed and Farooqui 1982), and cyanide levels 1 hour 37 2. HEALTH EFFECTS after exposure were 3,380 pg/g in liver, 748 ng/g in brain, and 550 pg/g in kidney. Cyanide levels ranged from 130-300% of controls in liver, brain, heart, and blood of mice exposed to potassium cyanide (1 g/mL) in the drinking water for 40 days (Buzaleh et al. 1989). Rabbits treated by gavage with hydrogen cyanide at 11.93-20.25 mg CN'/kg had blood and serum cyanide levels of 480 and 252 pg/dL, respectively, and tissue levels (ng/100 g) of 512 in liver, 83 in kidney, 95 in brain, 105 in the heart, 107 in the lung, and 72 in the spleen (Ballantyne 1983a). Cyanide has not been shown to accumulate in the blood and tissues following chronic oral exposure. Following the treatment of rats with hydrogen cyanide in the diet at <10.4 mg CN'/kg/day for 2 years, virtually no cyanide was found in plasma or kidneys (Howard and Hanzal 1955). Low levels were found in erythrocytes (mean of 1.9 pg/100 g). Increased levels of thiocyanate, the less toxic primary metabolite of cyanide, were found in plasma (1,123 pg/100 g), erythrocytes (246 pg/100 g), liver (665 pg/100 g), and kidney (1,188 pg/100 g). 2.3.2.3 Dermal Exposure No studies were located regarding distribution in humans after dermal exposure to cyanide. Rabbits exposed dermally to 33.75 mg CN/kg as hydrogen cyanide had blood and serum cyanide levels of 310 and 144 pg/dL, respectively, and tissue levels (pg/100 g) of 26 in liver, 66 in kidney, 97 in brain, 110 in heart, 120 in lungs, and 21 in spleen (Ballantyne 1983a). Cyanide concentrations were measured immediately after rabbits died from administration of 5 mg CN/kg as hydrogen cyanide, sodium cyanide, or potassium cyanide to their conjunctival sac (Ballantyne 1983b). Higher cyanide levels were observed in whole blood than in serum in all three groups. However, blood and serum cyanide levels were significantly lower in sodium cyanide and potassium cyanide groups than in the hydrogen cyanide group. Hydrogen cyanide treated rabbits also had higher concentrations of cyanide in myocardium, lungs, and brain than rabbits from the other two groups. In all groups, the least amount of cyanide was found in the liver and kidney. 2.3.3 Metabolism Numerous reports regarding accidental and/or intentional ingestion of cyanides by humans or regarding occupationally exposed individuals (see Section 2.5.1) suggest that cyanide is transformed into thiocyanate in humans, as is the case in experimental animals (see below). A plasma half-life of 20 minutes to 1 hour has been estimated for cyanides in humans after nonlethal exposures (Hartung 1982). The metabolism of cyanide has been studied in animals. The proposed metabolic pathways shown in Figure 2-3 are (1) the major pathway, conversion to thiocyanate by either rhodanese or 3-mercaptopyruvate; (2) conversion to 2-aminothiazoline-4-carboxylic acid; (3) incorporation into a 1-carbon metabolic pool; or (4) combining with hydroxocobalamin to form cyanocobalamin (vitamin B,;) (Ansell and Lewis 1970). Conversion of cyanide to thiocyanate is enhanced when cyanide poisoning is treated by intravenous administration of a sulfur donor (Way 1984). The sulfur donor must have a sulfane sulfur, a sulfur bonded to another sulfur (e.g., sodium thiosulfate). During conversion by rhodanese, a sulfur atom is transferred from the donor to the enzyme, forming a persulfide intermediate. The persulfide sulfur is then transferred from the enzyme to cyanide, yielding thiocyanate. Thiocyanate is then readily excreted in the urine as the major metabolite. Once the reaction-forming thiocyanate occurs, it is essentially irreversible. Radioisotopic studies showed that albumin interacts with the sulfane pool and that the serum albumin-sulfane sulfur carrier complex can react with cyanide (Schneider and Westley 1969). Higher hepatic rhodanese and lower serum albumin levels were found in mice fed a protein-free diet for 14 days compared with mice fed a control 38 2. HEALTH EFFECTS FIGURE 2-3. Basic Processes Involved in the Metabolism of Cyanide* MAJOR PATH (80%) CN ————p CNS: —o—p EXCRETED (INGESTED) MINOR PATH 2-AMINOTHIAZOLINE- CN- 4——— CYANOCOBALAMIN 4-CARBOXYLIC ACID & (POOL) (VITAMIN B15) 2-IMINOTHAZOLIDINE- 4-CARBOXYLIC ACID HONO HON HCOOH ——= METABOLISM (IN EXPIRED AIR) OF ONE-CARBON COMPOUNDS Co, FORMATES SOME EXCRETED IN URINE * Source: Ansell and Lewis 1970 1151054 39 2. HEALTH EFFECTS diet (Rutkowski et al. 1985). Despite the higher rhodanese levels, mortality following an intraperitoneal injection of sodium cyanide was higher in mice fed the protein-free diet both with and without thiosulfate pretreatment. In mice fed the control diet in reduced amounts, serum albumin levels were higher than controls. Mortality in food-deprived mice was higher compared with controls, but only at high cyanide doses when thiosulfate was also administered. These results suggested that serum albumin is not important in the detoxification of cyanide in VIVO. The species and tissue distribution of rhodanese is highly variable (Himwich and Saunder 1948). In dogs, the highest activity of rhodanese was found in the adrenal gland, =2.5 times greater than the activity in the liver. Monkeys, rabbits, and rats had the highest rhodanese activity in the liver and kidney, with relatively low levels in the adrenals. It should be noted that total rhodanese activity in other species was higher than in dogs, which is consistent with the greater susceptibility of dogs to the acute effects of cyanide. Similar activities of the enzyme among the species were found for the brain, testes, lungs, spleen, and muscle. In vitro studies with rat tissues indicated that rhodanese activity was =7 times higher in the nasal mucosa than in the liver (Dahl 1989). Furthermore, kinetic constants for rhodanese in mitochondria were higher in nasal than in liver tissue. Figure 2-4 illustrates the minor pathway for the metabolism of cyanide in mammalian systems in which cyanide chemically combines with the amino acid cystine. This chemical reaction yields cysteine and B-thiocyanoalanine that is further converted to form 2-aminothiazoline-4-carboxylic acid and its tautomer, 2-iminothiazolidiene- 4-carboxylic acid. Reactions of cyanide with the salts or esters of some amino acids (e.g., pyruvate, a-ketoglutarate, oxaloacetate) lead to the formation of cyanohydrin intermediates and their incorporation into intermediary metabolism. The ability of cyanide to form complexes with some metallic ions is the basis for the reaction with hydroxocobalamin that yields cyanocobalamin. Cyanocobalamin (vitamin B,,) is essential for the healthy development of mammalian organisms. The acute toxicity of cyanide may result from histotoxic anoxia through inhibition of cytochrome oxidase (Way 1984), which functions as the terminal oxidase of the mitochondrial respiratory chain. A two-step process has been proposed: cyanide first penetrates a protein crevice of cytochrome oxidase and binds to the protein. It then binds to the trivalent iron ion of the enzyme, forming a relatively stable coordination complex. As a result, the enzyme becomes unable to catalyze the reactions in which electrons would be transferred from reduced cytochrome to oxygen. Cellular oxygen utilization is thus impaired, with a resultant reduction in or cessation of aerobic metabolism (Rieders 1971; Way 1984). Glucose catabolism then shifts from the aerobic pathway to anaerobic metabolism including the pentose phosphate pathway, resulting in increased blood glucose, pyruvic acid, lactic acid, and nicotinamide adenine dinucleotide (NADPH) levels, and a decrease in the adenosine triphosphate/adenosine diphosphate (ATP/ADP) ratio (Rieders 1971; Way 1984). 2.3.4 Excretion 2.3.4.1 Inhalation Exposure Following chronic occupational exposure to 0.19-0.75 ppm hydrogen cyanide, 24-hour urinary levels of cyanide were 6.23 (smokers) and 5.4 pg/mL (nonsmokers) in exposed workers as compared with 3.2 (smokers) and 2.16 pg/mL (nonsmokers) in the controls (Chandra et al. 1980). 40 2. HEALTH EFFECTS FIGURE 2-4. Minor Path for the Removal of Cyanide from the Body* NH» NH» joe CN- jee ————————————— co S — CH — CH — COOH CN J /3-THIOCYANOALANINE CYSTINE NH» NH | 1 C C /N\ - / \ S N — S NH CH, — CH — COOH CH, — CH — COOH 2-AMINOTHIAZOLINE-4- 2-IMINO-4-THIAZOLIDINE- CARBOXYLIC ACID CARBOXYLIC ACID * Source: Ansell and Lewis 1970 115105-5 41 2. HEALTH EFFECTS No studies were located regarding excretion of cyanide in animals after inhalation exposure to cyanide. 2.3.4.2 Oral Exposure Cyanide metabolites are excreted primarily in urine, with small amounts eliminated through the lungs. The urinary excretion of thiocyanate was monitored in a man after ingestion of =3-5 g potassium cyanide (15-25 mg CN'/kg) (Liebowitz and Schwartz 1948). The results indicated that the patient excreted 237 mg of thiocyanate over a 72-hour period. This quantity was substantially more than the normal average amount of thiocyanate in urine, which varies between 0.85 and 14 mg/24 hours. When rats were given 2 mg CN/kg as radioactively labeled potassium cyanide, urinary excretion of radioactivity reached 47% of the dose within 24 hours following the administration (Farooqui and Ahmed 1982). When radioactively labeled sodium cyanide was injected subcutaneously into rats, no difference in radioactivity eliminated was observed between the group pretreated for 6 weeks with a diet containing 0.7 mg CN/kg as potassium cyanide and their matching controls (Okoh 1983). Most of the radioactivity was detected in the urine (89% by 24 hours). Thiocyanate was the major metabolite. About 4% of the radioactivity was expired, mostly as carbon dioxide. 2.3.4.3 Dermal Exposure No studies were located regarding excretion in humans or animals after dermal exposure to cyanide. 2.4 RELEVANCE TO PUBLIC HEALTH Data are available regarding health effects in humans and animals after inhalation, oral, and dermal exposure to cyanide. Cyanide is a highly toxic chemical that can produce death in humans and animals rapidly. This characteristic has long been recognized and, therefore, cyanide has often been used with suicidal and homicidal intent and in wars as a chemical warfare agent. Of the cyanide compounds, hydrogen cyanide, sodium cyanide, and potassium cyanide are the most common ones in the environment, with gaseous hydrogen cyanide being present in air. Cyanide can be formed during some chemical processes used in industry (for further information see Chapter 4). Dietary sources of cyanide are plants that contain cyanogenic glycosides such as cassava roots and fruit pits and juices. Sufficient concentrations of cyanide cause histotoxic hypoxia in the organism. The toxicity is due to the inability of the tissues to use oxygen. Due to this effect, oxygen tension is usually high in victims of cyanide poisoning, because oxygen transport is not affected. The primary target organs for acute cyanide toxicity are the central nervous system and the heart. Signs of toxicity in acute cyanide poisoning are tachypnea, incoordination of movements, cardiac irregularities, convulsions, coma, respiratory failure, and death. These effects are common to both humans and animals. Furthermore, a great similarity exists among cyanide-induced effects following inhalation, oral, and dermal exposure. The target organs of chronic cyanide toxicity are the central nervous system and thyroid gland. No studies were located regarding developmental and reproductive effects in humans after exposure to cyanide. However, oral studies in animals indicate possible fetotoxic effects. No studies were located regarding carcinogenic effects of cyanide. Death. The signs of cyanide toxicity at concentrations leading to death are well described. Intoxication at 22,000 ppm hydrogen cyanide is characterized by a brief sensation of dryness and burning in the throat due to local irritation, a suffusing warmth, and a hunger for air (Rieders 1971). Hyperpnea, and sometimes a brief outcry, follows the first breath. In <1 minute, apnea, a few gasps, collapse, and convulsions occur. 42 2. HEALTH EFFECTS Cardiovascular failure may also occur, although the heart may continue to beat for 3-4 minutes after the last breath. Reported signs include a rose-colored hue of the skin and a bitter, almond-like odor on the breath. The total absorbed dose of hydrogen cyanide in such rapid deaths can be as low as 0.7 mg/kg. Similar signs were reported following ingestion of high doses of cyanide. Within a few minutes after swallowing the toxicant, the victim collapses, frequently with a scream (Gettler and St. George 1934). Dyspnea, convulsions, and death from asphyxia follow. Dermal exposure to cyanide results in comparable effects. Based on case report studies, average fatal doses for humans were estimated in humans for inhalation (McNamara 1976), oral (EPA 1987a), and dermal (Rieders 1971) routes as 546 ppm, 1.52 mg/kg, and 100 mg/kg, respectively. In general, signs of toxicity preceding death are the same in humans and animals. Dyspnea, convulsions, and asphyxiation occur in animals following all routes of exposure to cyanide. LCs, values were provided for inhalation exposure to hydrogen cyanide in rats (Ballantyne 1983; Higgins et al. 1972), mice (Higgins et al. 1972; Matijak-Schaper and Alaric 1982), rabbits (Ballantyne 1983), cats, and goats (Berge et al. 1986). Lethal concentrations were also reported in dogs (Haymaker et al. 1952; Valade 1952). It has been demonstrated that lower cyanide concentrations resulted in death within a longer period of time and vice versa. The difference in species susceptibility to cyanide poisoning was indicated by lower lethal concentrations in rabbits compared with rats. Following oral exposure in animals, LD, values were calculated for rats dosed with cyanide as sodium cyanide (Ballantyne 1988; Smyth et al. 1969) and in rabbits treated with cyanide as hydrogen cyanide, sodium cyanide, and potassium cyanide (Ballantyne 1983). The mortality varied depending on the cyanide compound used. Cyanide toxicity was influenced by dilution of gavage doses. The higher the dilution, the higher the mortality. Mortality was observed following dermal exposure to hydrogen cyanide, sodium cyanide, and potassium cyanide (Ballantyne 1983a). The lowest LDy, indicating the highest toxicity, was calculated for cyanide applied to the skin in the form of hydrogen cyanide. Potassium cyanide was the least toxic compound. A similar pattern in cyanide toxicity was observed among these three compounds when applied into the inferior conjunctival sac of rabbits (Ballantyne 1983a, 1983b). Dermal absorption and consequently mortality was also observed in guinea pigs (Fairley et al. 1934; Walton and Witherspoon 1926) and in dogs (Walton and Witherspoon 1926) following unspecified doses of hydrogen cyanide. Cyanide absorption and, therefore, toxicity differed in rabbits with dry intact, moist, or abraded skin (Ballantyne 1988). The lowest LDs, for cyanide given as sodium cyanide was calculated for rabbits with abraded skin. The mechanism of cyanide toxicity has been described (Way 1984). Cyanide inhibits enzymatic activity by binding to the metallic cofactor in metalloenzymes. Cytochrome oxidase (an enzyme in the mitochondrial respiratory chain) is sensitive to cyanide action. Due to its inhibition, oxygen cannot be used and histotoxic hypoxia develops (see Section 2.3.3). The inhibition of oxygen use by cells causes oxygen tensions to rise in peripheral tissues; this results in a decrease in the unloading gradient for oxyhemoglobin. Thus, oxyhemoglobin is carried in the venous blood, causing it to be nearly as red as the arterial blood (Rieders 1971). Inhibition of oxygen utilization is thought to occur rapidly after cyanide exposure. Inhibition of cytochrome oxidase activity peaked 5-10 minutes following the intraperitoneal administration of potassium cyanide to mice, rats, and gerbils (Schubert and Brill 1968). In addition to binding to cytochrome oxidase, cyanide binds to catalase, peroxidase, methemoglobin, hydroxocobalamin, phosphatase, tyrosinase, ascorbic acid oxidase, xanthine oxidase, and succinic dehydrogenase. These reactions may make contributions to cyanide’s toxicity (Ardelt et al. 1989; Rieders 1971). Signs of cyanide intoxication include an initial hyperpnea followed by dyspnea and then convulsions (Rieders 1971; Way 1984). 43 2. HEALTH EFFECTS These effects are due to initial stimulation of carotid and aortic bodies and effects on the central nervous system. Death is caused by respiratory collapse resulting from central nervous system toxicity. Cyanides are highly toxic chemicals that should be handled only by properly trained personnel with appropriate protective equipment using extreme caution. Death can result from exposure by all routes that humans are likely to experience, including transocular. Although cyanides are among the most acutely toxic of all industrial chemicals, are produced in large quantities, and used in many applications, they cause few serious accidents or deaths (Hartung 1982). This appears to be due to the fact that it is common knowledge that the cyanides are very toxic materials that need to be treated with caution. Systemic Effects Respiratory Effects. Respiratory effects commonly occur after cyanide poisoning by any route of exposure. Following inhalation exposure, the first breath of a lethal concentration of hydrogen cyanide causes hyperpnea (Rieders 1971). The victims experience shortness of breath that may be rapidly (within <1 minute) followed by apnea. Dyspnea was reported in patients who survived acute inhalation exposure to cyanide (Chen and Rose 1952; Peden et al. 1986; Potter 1950). Similarly, dyspnea was observed in humans following acute oral exposure to cyanide as sodium cyanide (Grandas et al. 1989), as potassium cyanide (Liebowitz and Schwartz 1948), or as cyanogenic glycosides in apricot pits (Lasch and El Shawa 1981). Likewise, dyspnea occurred following dermal exposure to cyanide as copper cyanide (Dodds and McKnight 1985), silver cyanide (Pontal et al. 1982), and potassium cyanide (Trapp 1970) in occupational accidents. Humans acutely exposed to cyanogen experienced nasal irritation (McNemey and Schrenk 1960). Various symptoms indicating respiratory effects were reported in humans exposed to cyanide in occupational settings. Upper respiratory irritation, cough, altered sense of smell, nasal congestion, epistaxis, hemoptysis, and dyspnea were among the clinical signs of cyanide toxicity (Blanc et al. 1985; Chandra et al. 1980; El Ghawabi et al. 1975). The severity of these effects correlated with cyanide levels in the working environment. It must be pointed out, however, that in occupational settings such as electroplating operations, exposure to other chemicals also occurs. No increased incidence of cases of pneumonia, bronchitis or other respiratory effects were reported in workers exposed to sodium cyanide over a period of 14 years (Du Pont 1971), but pulmonary function was not examined and numerous design limitations greatly decreased the validity of the results. Cyanide exposure by any route also produces similar respiratory effects in animals. Cardiovascular Effects. Hypotension was the main effect reported in patients after acute inhalation exposure to cyanide (Chen and Rose 1952; Peden et al. 1986), as well as after oral exposure to potassium cyanide (Liebowitz and Schwartz 1948) or to cyanogenic glycosides in apricot pits (Lasch and El Shawa 1981). Palpitations were recorded in men exposed dermally to hydrogen cyanide (Drinker 1932). Peripheral vasoconstriction and gross plasma extravasation were found in a man whose whole body was exposed to liquid copper cyanide in a cistern (Dodds and McKnight 1985). In many of these cases the effects reported may reflect an indirect action mediated by the nervous system. Most individuals experienced marked sinus irregularities and a slowing of heart rate immediately after an intravenous injection of cyanide as sodium cyanide in man (Wexler et al. 1947). Workers exposed to cyanide during electroplating and silver-reclaiming jobs complained of precordial pains (Blanc et al. 1985; El Ghawabi et al. 1975). During electroplating operations, however, exposure to other chemicals such as cleaners and cutting oils also occurs. In workers exposed to sodium cyanide during a 14-year period there was a small increase in the expected number of myocardial infarctions, but the difference relative to unexposed controls was not statistically significant (Du Pont 1971). The latter study, however, suffers from design limitations, which may have rendered the results inconclusive. 44 2. HEALTH EFFECTS Acute inhalation exposure to hydrogen cyanide resulted in bradycardia, arrhythmia, and T-wave abnormalities (Purser et al. 1984), and increased cardiac specific creatinine phosphokinase activity (O'Flaherty and Thomas 1982) in monkeys. Isolated strips of aorta from rabbits, dogs, and ferrets were used to determine the effects of cyanide on vascular smooth muscle (Robinson et al. 1985b). Cyanide was found to cause small contractions in the isolated rabbit aorta at low cyanide concentrations; at higher cyanide concentrations, relaxation occurred. It was found that chlorpromazine or 4,4’-diisothiocyano-2,2’-stilbene disulfonic acid (DIDS) reduced the contractions (Robinson et al. 1985a). The results of in vitro studies suggest an interaction between calcium ions and cyanide in cardiovascular effects. It has been demonstrated that exposure to cyanide in a metabolically depleted ferret papillary muscle eventually results in elevated intracellular calcium levels, but only after a substantial contracture develops (Allen and Smith 1985). The authors proposed that intracellular calcium may precipitate cell damage and arrhythmias. The mechanism by which calcium levels are raised was not determined. Gastrointestinal Effects. The information regarding gastrointestinal effects after inhalation and dermal exposure to cyanide is limited. Nausea and vomiting were reported in workers exposed to cyanide occupationally (Blanc et al. 1985: El Ghawabi et al. 1975). Similarly, exposure to hydrogen cyanide caused vomiting in dogs (Valade 1952). The only information on dermal exposure was provided in a study with guinea pigs (Fairley et al. 1934). Exposure to hydrogen cyanide produced submucous hemorrhages in the stomach. Following oral exposure, the recorded effects included vomiting in patients after acute exposure to cyanogenic glycosides in apricot pits (Lasch and El Shawa 1981), gastrointestinal spasms after exposure to cyanide in the form of potassium cyanide (Thomas and Brooks 1970), and gastric necrosis after ingestion of sodium cyanide (Grandas et al. 1989). Furthermore, frequent vomiting was observed in pigs orally exposed to low doses of cyanide as potassium cyanide (Jackson 1988). The gastrointestinal effects can be caused by central nervous system stimulation (nausea) or by direct contact (necrosis) with cyanide salts. Hematological Effects. No pathological changes were found during hematological examinations of an individual following ingestion of 15 mg CN/kg as potassium cyanide (Liebowitz and Schwartz 1948). However, increased hemoglobin and lymphocyte counts were found in workers occupationally exposed to 6.4-10.4 ppm cyanide (El Ghawabi et al. 1975). It is possible, however, that chemicals other than cyanide may have contributed to the effects observed in occupationally exposed subjects. Increases in the mean corpuscular volume of erythrocytes and of hemoglobin concentration suggested hematological effects in rats after exposure to potassium silver cyanide for 90 days (Gerhart 1987). Decreased hematocrit, erythrocyte count, and hemoglobin concentration were found in rats treated with copper cyanide by gavage during intermediate-duration exposure; however, because of the known hematotoxic properties of copper, these effects could be attributed to copper rather than to cyanide (Gerhart 1986). Furthermore, increased hematopoiesis was reported following chronic exposure to sodium cyanide in dogs (Hertting et al. 1960), but the study was limited by the number of animals used. Thus, there is some evidence that cyanide stimulates erythrocyte production; this is reasonable since anoxia will do the same. Musculoskeletal Effects. Convulsions are typical symptoms of cyanide poisoning after inhalation (Rieders 1971), oral (Gettler and St. George 1934; Haymaker et al. 1952), or dermal exposure (Ballantyne 1988; Fairley et al. 1934; Walton and Witherspoon 1926). The convulsions indicate involvement of the central nervous system. Furthermore, muscular rigidity was reported after acute inhalation (Haymaker et al. 1952) and oral (Grandas et al. 45 2. HEALTH EFFECTS 1989) exposure to high levels of cyanide. Skeletal muscle participates significantly in cyanide biotransformation in vitro (Devlin et al. 1989a). In muscles sectioned longitudinally, points of rhodanese staining were associated with the mitochondria site within the fiber. Cyanide clearance in the isolated hindlimbs of rats was only 1.5 times lower than in the liver (Devlin et al. 1989b). However, muscular effects observed in cyanide poisoning victims probably reflect cyanide toxicity to the central nervous system. Hepatic Effects. No studies were located regarding hepatic effects in humans after exposure to cyanide by any route. Limited information was obtained in animals. The increased bilirubin, alkaline phosphatase, SGOT and SGPT levels, necrosis, and decreased globulin levels found in the blood of male rats that were dosed with cyanide as copper cyanide may have been due to the toxicity of copper (Gerhart 1986). No hepatic effects were found in rats gavaged with potassium silver cyanide for the same time period (Gerhart 1987) or in rats fed for 2 years with a diet fumigated with hydrogen cyanide (Howard and Hanzal 1955). Furthermore, no effects were recorded in rats and monkeys following 6 months inhalation exposure to cyanogen (Lewis et al. 1984). In vitro studies indicated that cyanide biotransformation in the liver is high because of the high rhodanese activity in the organ (Devlin et al. 1989a). Cyanide extraction ratios and rates of thiosulfate generation were established in isolated rat livers (Devlin et al. 1989b). Cyanide clearance was =1.5 times greater in the liver (calculated for the total mass) as in the skeletal muscle. Adding sodium thiosulfate to the system quickly increased the conversion of cyanide to thiocyanate. Interspecies differences in the rhodanese activity in the liver were reported in animals (Drawbaugh and Marrs 1987). The activity was highest in rats, hamsters, and guinea pigs, followed by rabbits, and lowest in marmosets and dogs. This variability can explain interspecies differences in sensitivity to cyanide toxicity demonstrated by different LCs, values. It is evident that the liver plays an important role in cyanide toxicokinetics and it can be anticipated, that following rhodanese inactivation, harmful effects to the liver tissue may be expected. Renal Effects. No studies were located regarding renal effects in humans after inhalation exposure to cyanide. Case reports cited transitory albuminuria in a man ingesting 15 mg CN/kg as potassium cyanide (Liebowitz and Schwartz 1948) and transitory oliguria in a man who accidentally fell into a cistern with copper cyanide (Dodds and McKnight 1985). Few studies cited renal effects in animals following oral exposure. Decreased kidney weight was observed in rats exposed to copper cyanide (Gerhart 1986) and increased blood urea nitrogen was found in rats exposed to potassium silver cyanide during the interim bleed, but not at the terminal bleed (Gerhart 1986) in the intermediate-duration experiments. Histopathological changes in glomerular cells were reported in pigs fed cassava roots for 110 days (Tewe and Maner 1981b) and in epithelial tubular cells in dogs exposed to sodium cyanide for 14.5 months (Hertting et al. 1960). However, no kidney effects were observed in rats after chronic oral exposure to hydrogen cyanide (Howard and Hanzal 1955) and in rats and monkeys after intermediate- duration inhalation exposure to cyanogen (Lewis et al. 1984). Interspecies differences in rhodanese activity in the kidney were found in several species; the differences were similar to those observed for the liver rhodanese activity (Drawbaugh and Marrs 1987). There is no conclusive evidence to support a nephrotoxic action of cyanide. Dermal/Ocular Effects. Acute exposure to cyanogen gas produced eye irritation in volunteers (McNemey and Schrenk 1960). Similarly, chronic exposure to cyanide in the working environment caused eye irritation in exposed individuals (Blanc et al. 1985). In addition, rashes developed in =42% of exposed workers. Following oral exposure in animals, discolored inguinal fur was observed in rats exposed to copper cyanide (Gerhart 1986) and potassium silver cyanide (Gerhart 1987) for an intermediate-duration period. In addition, exposure to potassium silver cyanide caused ocular opacity in exposed animals, but corneal opacity is also a sign of excessive exposure to soluble silver salts alone. No dermal lesions were observed in rabbits exposed dermally to cyanogen (McNerney and Schrenk 1960) and vascular congestion was reported in guinea pigs exposed to hydrogen cyanide 46 2. HEALTH EFFECTS (Fairley et al. 1934). However, when cyanide was applied to a rabbit’s eye, keratitis developed regardless of the chemical form of cyanide used (Ballantyne 1983). Other Systemic Effects. Thiocyanate, a metabolite of cyanide, is goitrogenic in animals and humans (VanderLaan and Bissel 1946). Although within normal limits, statistically significant increased levels of TSH found in workers exposed to cyanide in a silver-reclaiming facility suggested thyroid effects (Blanc et al. 1985). Furthermore, increased '*'I uptake and enlarged thyroid glands were seen in workers exposed to cyanide during electroplating (E1 Ghawabi et al. 1975). Exposure to other chemicals such as cleaners and cutting oils also occurs during electroplating operations. High incidences of endemic goiter (Delange and Ermans 1971) and a decreased uptake of radioiodine (Cliff et al. 1986; Delange and Ermans 1971) were associated with chronic oral exposure to cyanogenic glycosides in cassava meals. Similar effects were observed in animals. Depressed thyroid gland function was diagnosed in rats that were exposed orally to potassium cyanide for an intermediate-duration period (Philbrick et al. 1979). In addition, thyroid gland hypofunction was reported in pigs treated with cassava (Tewe and Maner 1981b) or with potassium cyanide (Jackson 1988) during intermediate-duration exposure. The mechanisms of cyanide-induced effects on the thyroid gland are discussed in several studies. Thiocyanate markedly inhibits accumulation of iodine by the thyroid gland, thus decreasing the ability of the gland to maintain a concentration of iodine above the blood’s (VanderLaan and Bissell 1946). In addition, thiocyanate may inhibit the iodination process, thus interfering with the organic binding of glandular iodine and reducing the formation of thyroxine (Ermans et al. 1972). Changes in thyroid chemistry reported in individuals chemically exposed to cyanide have not been accompanied by manifestations of hypothyroidism. Decreased body weight was reported in workers occupationally exposed to hydrogen cyanide (Blanc et al. 1985). Weight loss was one of several effects in this particular group of workers who were in poor health due to chronic cyanide exposure, but other chemicals such as cleaners and cutting oils may have contributed to this effect. Decreased weight was recorded in rats after inhalation exposure to cyanogen for 6 months (Lewis et al. 1984), and decreased weight gain was found in male rats after intermediate-duration oral exposure to copper cyanide (Gerhart 1986) and potassium silver cyanide (Gerhart 1987). The changes in body weight are associated with cyanide toxicity. A dose-dependency was observed in some experiments (Gerhart 1986). In all cases cited above, the effects on body weight were seen only in male animals. No body weight effects were observed in female rats (Gerhart 1986, 1987) or female pigs (Tewe and Maner 1981b) exposed orally for an intermediate-duration period. Therefore, male animals appear to be more susceptible. Immunological Effects. No studies were located regarding immunological effects in humans and animals after cyanide exposure by any route. Therefore, the potential for cyanide to cause immunological effects in humans exposed in the environment or at hazardous waste sites cannot be assessed. Neurological Effects. The central nervous system is the primary target for cyanide toxicity in humans and animals. Acute inhalation of high concentrations of cyanide provokes a brief central nervous system stimulation followed by depression, convulsions, coma, and death. The picture is comparable in humans (Bonsall 1984; Chen and Rose 1952; Peden et al. 1986; Potter 1950; Singh et al. 1989) and in animals (Haymaker et al. 1952; McNerney and Schrenk 1960; Purser et al. 1984; Valade 1952). The effects are probably due to rapid biochemical changes in the brain, such as changes in ion flux, neurotransmitter release, and possibly peroxide formation (Johnson and Isom 1987; Kanthasamy et al. 1991a; Persson et al. 1985). Chronic exposure to lower cyanide concentrations in occupational settings causes a variety of symptoms from fatigue, dizziness, headaches (Blanc et al. 1985; Chandra et al. 1988; El Ghawabi et al. 1975) to ringing in the ears, paresthesias of extremities, and syncopes (Blanc et al. 1985), or even hemiparesis and hemianopia (Sandberg 47 2. HEALTH EFFECTS 1967). In addition, behavioral changes were reported following prolonged cyanide exposure in humans (Chandra et al. 1988) and in animals (Lewis et al. 1984). It is possible, however, that occupational exposure, such as during electroplating operations, chemicals other than cyanide may have contributed to the effects observed. The severity of neurological effects in humans after acute oral exposure to cyanide are dose-related. The symptoms vary from tremor and headache (Chen and Rose 1952; Lasch and El Shawa 1981) to deep coma (Lasch and El Shawa 1981; Thomas and Brooks 1970). Due to pathological lesions that may develop in the central nervous system during acute exposure to high doses, complications can develop during the recovery. Severe parkinsonism was one of the effects resulting from severe acute oral exposure to cyanide (Carella et al. 1988; Grandas et al. 1989; Rosenberg et al. 1989; Uitti et al. 1985). Chronic exposure to cyanogenic glycosides in cassava meals lead to multiple neuropathies in exposed individuals (Howlett et al. 1990; Ministry of Health, Mozambique 1984; Monekosso and Wilson 1966; Money 1958; Osuntokun 1968, 1972; Osuntokun et al. 1969). Among those observed were hyperreflexia or spastic paraparesis of the extremities, spastic dysarthria, visual and hearing difficulties, and cerebellar signs. It should be mentioned, however, that a recent study reported the isolation of scopoletin, a potent hypotensive and spasmolytic agent, from cassava roots (Obidoa and Obasi 1991). This substance, which remains in cassava during processing, rather than cyanide, was suggested to be the etiological agent in the tropical ataxic neuropathy observed among cassava eaters (Obidoa and Obasi 1991). Depending on the dose of cyanide given to animals, neurological effects of varying severity occurred. Tremors, convulsions, and lethargy were seen in rats treated with potassium silver cyanide during intermediate-duration exposure (Gerhart 1987). Depressed activity was the only neurological sign found in rats exposed to copper cyanide for the same period, but with lower doses of total cyanide (Gerhart 1986). Myelin degeneration of spinal cord tracts was found in rats treated with potassium cyanide for 11.5 months (Philbrick et al. 1979). Similar to inhalation exposure effects, behavioral changes were found in pigs following intermediate-duration oral exposure to cyanide as potassium cyanide (Jackson 1988). In many studies, however, neurological effects occurred at high cyanide exposure levels. Extensive degenerative changes have been produced experimentally in the brain by cyanide treatment (Haymaker et al. 1952; Hirano et al. 1967; Levine 1969; Levine and Stypulkowski 1959a, 1958b). Convulsions and coma were also reported in humans (Dodds and McKnight 1985; Trapp 1970) and in animals (Fairley et al. 1934; Walton and Witherspoon 1926) following acute dermal exposure to cyanide. The nervous system is the most sensitive target for cyanide toxicity, partly because of its high metabolic demands. High doses of cyanide can result in death via central nervous system effects, which can cause respiratory arrest. In humans, chronic low-level cyanide exposure through cassava consumption (and possibly through tobacco smoke inhalation) has been associated with tropical neuropathy, tobacco amblyopia, and Leber’s hereditary optic atrophy. It has been suggested that defects in the metabolic conversion of cyanide to thiocyanate, as well as nutritional deficiencies of protein and vitamin B,,, play a role in the development of these disorders (Wilson 1965). Rats treated with sodium cyanide subcutaneously developed necrotic lesions of the corpus callosum and optic nerve (Lessell 1971). High mortality was observed among exposed animals. Additional inhalation and oral studies in animals have shown that cyanide exposure leads to encephalopathy in both white and gray matter. In particular, damage has been observed in regions such as the deep cerebral white matter, the corpus callosum, hippocampus, corpora striata, palladium, and the substantia nigra. White matter may be more sensitive because of its relatively low cytochrome oxidase content. These effects have been observed following acute exposures (Levine and Stypulkowski 1959a, 1959b) and chronic exposures (Hertting et al. 1960). It appears that necrosis is the most prevalent effect following acute exposure to high concentrations of cyanide, whereas demyelination is observed in animals that survive repeated exposure protocols (Bass 1968; Ibrahim et al. 1963). The mechanism 48 2. HEALTH EFFECTS of demyelination is not completely understood, but the experimental evidence suggests that a direct effect of cyanide on white matter may not be necessary. It has been suggested that local edema affecting the olygodendrocytes and caused by vascular changes triggered by cyanide represent a primary event in demyelination (Bass 1968; Ibrahim et al. 1963). One characteristic of cyanide intoxication appears to be the inability of tissues to utilize oxygen. Consistent with this view is a report that in cyanide-intoxicated rats arterial pO, levels rose while carbon dioxide levels fell (Brierley et al. 1976). The authors suggested that the low levels of carbon dioxide may have led to vasoconstriction and reduction in brain blood flow; therefore brain damage may have been due to both histotoxic and anoxic effects. Partial remyelination after cessation of exposure has been reported, but it is apparent that this process, unlike the peripheral nervous system, is slow and incomplete (Hirano et al. 1968). The topographic selectivity of cyanide-induced encephalopathy may be related to the depth of acute intoxication and the distribution of the blood flow, which may result in selected regions of vascular insufficiency (Levine 1969). Several recent studies have suggested that a disruption in neuronal calcium regulation may be an important factor in the manifestation of cyanide-induced neurotoxic events following acute exposure. The predominance of anaerobic metabolism in a cyanide-poisoned cell induces a decrease in the ATP/ADP ratio, or energy charge (Isom et al. 1975), and thus alters energy-dependent processes such as cellular calcium homeostasis (Johnson et al. 1986). Elevated levels of intracellular calcium in a cyanide-exposed, presynaptic squid neuron were observed in an in vitro study (Adams et al. 1985). Elevated levels of neuronal calcium may initiate the release of neurotransmitters from the presynaptic terminal, which can activate the nervous system (Maduh et al. 1990a). Levels of whole-brain calcium increased when potassium cyanide was administered subcutaneously to mice. Brain injury may be associated with cyanide-induced glutamate release, which in turn, produces excitotoxic responses in select brain areas (Patel et al. 1992). These increases were correlated with cyanide-induced tremors (Johnson et al. 1986). Increases in intracellular calcium have also been associated with cyanide-induced effects on vascular smooth muscle and cardiac muscle, possibly inducing cell damage (Allen and Smith 1985; Robinson et al. 1985a). These effects may result from ischemia-induced increases in extracellular potassium, which in turn enhance cellular permeabilities to cyanide (Robinson et al. 1985b). Furthermore, changes in the cytosolic pH and a dysfunction of hydrogen ion handling mechanisms were observed in neuronal cells exposed in vitro to cyanide (Maduh et al. 19900). Recent studies have shown that cyanide induces the release of catecholamines from rat pheochromocytoma cells and brain slices (Kanthasamy et al. 1991b), from isolated bovine adrenal glands (Borowitz et al. 1988), and from the adrenals of mice following subcutaneous injection of high doses of potassium cyanide (Kanthasamy et al. 1991). Thus, it was proposed that the cardiac and peripheral autonomic responses to cyanide are partially mediated by an elevation of plasma catecholamines (Kanthasomy et al. 1991b). Developmental Effects. No studies were located regarding developmental effects in humans after any route of exposure and in animals after inhalation and dermal exposure. However, studies in rats (Singh 1981) and hamsters (Frakes et al. 1986) fed a cassava diet suggested that cyanide may have teratogenic and fetotoxic effects, but Singh (1981) indicated that the results should be interpreted with caution due to the preliminary nature of the report and also indicated that the effects could have been due to the low protein content of the cassava diet. In contrast, Frakes et al. (1986) clearly showed that the cyanogenic glycosides in the cassava diet were responsible for the adverse developmental effects, since a group of animals fed a diet that resembled cassava in nutritional value, but lacked the cyanogenic glycosides, had only reduced body weight and did not exhibit increased runting or decreased ossification. Similarly, treating hamsters with D,L-amygdalin produced teratogenic effects (Willhite 1982). Furthermore, subcutaneous infusions of sodium cyanide to pregnant hamsters increased the incidences of neural tube defects in the offspring (Doherty et al. 1982). In contrast, no teratogenic effects were reported in rats (Tewe and Maner 1981a) and in pigs (Tewe and Maner 1981b) exposed to cassava alone 49 2. HEALTH EFFECTS or supplemented with potassium cyanide. The only effect was decreased growth in weanling rats of cyanide exposed dams in a two generation exposure study (Tewe and Maner 1981a). In contrast to oral exposure, no teratogenic effects were observed in hamsters that received d,l-amygdalin intravenously (Willhite 1982). The teratogenic effects observed after oral amygdalin exposure may have been due to cyanide released by bacterial beta glucosidase in the gastrointestinal tract. The possibility that cyanide could cause developmental effects in humans cannot be ruled out. Reproductive Effects. The information regarding reproductive effects following cyanide exposure is limited. No studies were located regarding reproductive effects in humans after any route of exposure. The only information regarding reproductive effects in animals was a report of increased resorptions following oral exposure of rats to cyanogenic glycosides in a cassava diet (Singh 1981) and a report of increased gonadal weight in male rats exposed to copper cyanide (Gerhart 1986) or potassium silver cyanide (Gerhart 1987) for 90 days. In contrast, no reproductive effects were reported in hamsters exposed to cassava during gestation (Frakes et al. 1986). The information is insufficient to determine whether cyanide exposure would lead to reproductive effects in humans. Genotoxic Effects. In vitro genotoxicity studies are summarized in Table 2-4. Cyanide in the form of potassium cyanide tested negative in Salmonella typhimurium strains TA1535, TA1537, TA1538, TA98, TA100 (DeFlora 1981), TA97, and TA102 (DeFlora et al. 1984). A positive mutagenic response was reported for hydrogen cyanide in strain TA100 without metabolic activation (Kushi et al. 1983). Adding S-9 mix to the culture decreased the induction of reverse mutations by cyanide to 40% of the nonactivated reaction. Negative results were also obtained in the DNA repair test in Escherichia coli WP67, CM871, and WP2 with potassium cyanide (DeFlora et al. 1984). Only one in vivo study was located. No testicular DNA-synthesis inhibition was detected in mice after a single oral dose of 1 mg/kg cyanide as potassium cyanide (Friedman and Staub 1976). The results indicate that cyanide, especially in a form of salts, is not mutagenic. Cancer. No studies were located regarding carcinogenic effects of cyanide exposure in humans or animals following any route of exposure. Therefore, no hypothesis can be made as to whether or not an increased risk of cancer can be expected in populations exposed to cyanide. 2.5 BIOMARKERS OF EXPOSURE AND EFFECT Biomarkers are broadly defined as indicators signaling events in biologic systems or samples. They have been classified as markers of exposure, markers of effect, and markers of susceptibility (NAS/NRC 1989). A biomarker of exposure is a xenobiotic substance or its metabolite(s) or the product of an interaction between a xenobiotic agent and some target molecule or cell that is measured within a compartment of an organism (NAS/NRC 1989). The preferred biomarkers of exposure are generally the substance itself or substance-specific metabolites in readily obtainable body fluid or excreta. However, several factors can confound the use and interpretation of biomarkers of exposure. The body burden of a substance may be the result of exposures from more than one source. The substance being measured may be a metabolite of another xenobiotic substance (e.g., high urinary levels of phenol can result from exposure to several different aromatic compounds). Depending on the properties of the substance (e.g., biologic half-life) and environmental conditions (e.g., duration and route of exposure), the substance and all of its metabolites may have left the body by the time biologic samples can be taken. It may be difficult to identify individuals exposed to hazardous substances that are commonly found in TABLE 2-4. Genotoxicity of Cyanide In Vitro Results With Without Species (test system) End point activation activation Reference Form Prokaryotic organisms: Salmonella typhimurium Reverse mutation - Not tested DeFlora 1984 TA82, TA102 S. typhimurium Reverse mutation - - DeFlora 1981 TA98, TA100, TA1535 TA1537, TA1538 S. typhimurium Reverse mutation Kushi et al. 1983 TA98 — —- TA100 (+) Escherichia coli DNA repair test - - DeFlora 1984 WP67, CM871, WP2 + Eukaryotic organisms: HeLa cells DNA synthesis inhibition —- - Painter and Howard 1982 KCN KCN HCN KCN KCN DNA = deoxyribonucleic acid; HCN = hydrogen cyanide; KCN = potassium cyanide; — = negative result; + = positive result; (+) = weakly positive result S103443 HLV3H 0S 51 2. HEALTH EFFECTS body tissues and fluids (e.g., essential mineral nutrients such as copper, zinc, and selenium). Biomarkers of exposure to cyanide are discussed in Section 2.5.1. Biomarkers of effect are defined as any measurable biochemical, physiologic, or other alteration within an organism that, depending on magnitude, can be recognized as an established or potential health impairment or disease (NAS/NRC 1989). This definition encompasses biochemical or cellular signals of tissue dysfunction (e.g., increased liver enzyme activity or pathologic changes in female genital epithelial cells), as well as physiologic signs of dysfunction such as increased blood pressure or decreased lung capacity. Note that these markers are often not substance specific. They also may not be directly adverse, but can indicate potential health impairment (e.g., DNA adducts). Biomarkers of effects caused by cyanide are discussed in Section 2.5.2. A biomarker of susceptibility is an indicator of an inherent or acquired limitation of an organism’s ability to respond to the challenge of exposure to a specific xenobiotic substance. It can be an intrinsic genetic or other characteristic or a preexisting disease that results in an increase in absorbed dose, biologically effective dose, or target tissue response. If biomarkers of susceptibility exist, they are discussed in Section 2.7, "Populations That Are Unusually Susceptible." 2.5.1 Biomarkers Used to Identify or Quantify Exposure to Cyanide Methods are available to measure levels of cyanide and its metabolite, thiocyanate, in blood and urine. High blood cyanide levels of 250-300 pg/100 mL were reported in cases of death from cyanide poisoning (Vogel et al. 1981). The relationship between increased exposure and increased urine levels of thiocyanate was demonstrated in workers exposed occupationally to 6.4-10.3 ppm cyanide in air (El Ghawabi et al. 1975). In another study, blood cyanide concentrations varied from 0.54 to 28.36 pg/100 mL in workers exposed to =0.2-0.8 ppm cyanide in air and from 0.0 to 14.0 pg/100 mL in control workers (Chandra et al. 1988). Correspondingly, blood thiocyanate concentrations were 0.05-2.80 mg/100 mL in exposed workers and 0.02-0.88 mg/100 mL in control workers, respectively. Data obtained from the controls indicate that cyanide can be detected in populations exposed to low cyanide levels in the environment. Cyanide-containing food, metabolism of certain drugs, and combustion of nitrogenous polymers are among several sources of cyanide exposure. Furthermore, industrially polluted air, soil, and water may contribute to higher environmental cyanide levels. In addition, several studies showed increased cyanide and thiocyanate levels in body fluids of smokers. The difference between smokers and nonsmokers can be quite distinct (Maliszewski and Bass 1955). Mean thiocyanate levels in plasma were found to be 710 and 196 pg/mL; in saliva, 7,566 and 2,031 pg/mL; and in urine, 12.26 and 2.10 mg/24 hours in smokers and nonsmokers, respectively. Whether it is more appropriate to use whole blood or plasma for measuring cyanide concentrations has been the subject of several reports. Cyanide plasma levels are usually about one-third to one-half, depending on the species, those of whole blood levels (Ballantyne 1983c). However, they can more closely reflect the actual tissue dose. Furthermore, cyanide was found to attach more readily to plasma albumin than to hemoglobin (McMillan and Svoboda 1982). It was suggested that hemoglobin in erythrocytes binds cyanide molecules, but does not play any role in their metabolism. Some authors argue cyanide in the red blood cells may be biologically active (Way 1984). In addition, it is known that cyanide rapidly leaves serum and plasma, especially in the first 20 minutes. It may be appropriate to measure cyanide in both whole blood and plasma. Whole blood samples can be stored at 4°C for several weeks. In cyanide-poisoning cases, any blood levels of cyanide >0.2 pg/L indicate a toxic situation (Berlin 1977). However, because cyanide binds tightly to cytochrome oxidase, serious effects can also occur at lower levels; therefore, the clinical condition of the patient should be considered when determining proper therapy. 52 2. HEALTH EFFECTS An almond-like smell in the breath of a poisoned patient can warn a physician that the individual may be suffering from cyanide poisoning. Approximately 60-70% of the population can detect the bitter almond odor of hydrogen cyanide. The odor threshold for those sensitive to the odor is estimated to be 1-5 ppm in the air. However, even at high toxic concentrations some individuals cannot smell hydrogen cyanide. Some effects of cyanide that can also be used to monitor exposure are discussed in Section 2.5.2. 2.5.2 Biomarkers Used to Characterize Effects Caused by Cyanide Cyanide inhibits enzymatic activity by binding to the metallic cofactor in metalloenzymes (Ardelt et al. 1989; Way 1984). Cytochrome oxidase is sensitive to cyanide inhibition. Consequent to the inhibition, oxygen cannot be used and histotoxic anoxia occurs. Death is caused by central nervous system depression as a result of the high sensitivity of brain tissue to anoxia. Dyspnea, palpitations, hypotension, convulsions, and vomiting are among the first effects of acute cyanide poisoning (see Section 2.2). Ingestion of amounts 250-100 mg sodium or potassium cyanide may be followed by almost instantaneous collapse and cessation of respiration (Hartung 1982). Data summarized by Hartung (1982) indicate that exposure to a concentration in the air of 270 ppm causes immediate death; concentrations of 181 ppm and 135 ppm are fatal after 10 and 20 minutes of exposure, respectively; concentrations between 45 and 55 ppm can be tolerated for 30-60 minutes with immediate or late effects; and 18-36 ppm may produce slight symptoms after several hours of exposure. Following chronic exposure, cyanide has been associated with the development of tropical neuropathy, tobacco amblyopia, and Leber’s hereditary optic atrophy (Wilson 1965). Chronic exposure to cyanide has also been connected with the occurrence of endemic goiter (Delange and Ermans 1971). 2.6 INTERACTIONS WITH OTHER CHEMICALS A number of compounds act in synergy with cyanide to produce toxic effects. Hydrogen cyanide may interact with other toxicants in smoke from fires (Birky and Clarke 1981). High blood cyanide levels were found in fire victims; however, the carboxyhemoglobin levels were also high. Thus, it is difficult to assess the significance of hydrogen cyanide in the toxicity. The authors suggested that sublethal concentrations of hydrogen cyanide may interact with other toxicants and cause death. They also speculated that cyanide could lead to incapacitation, preventing escape, so that the victim could be exposed to high levels of carbon monoxide. In an investigation to examine toxicological interactions of the primary fire gases, the additive, synergistic, or antagonistic effects of combinations of hydrogen cyanide with carbon monoxide or with carbon dioxide on the 30-minute LCs, value for hydrogen cyanide alone were determined in rats (Levin et al. 1987). Coexposure of the rats to hydrogen cyanide (LCs,=110 ppm) and carbon monoxide (LCs3=4,600 ppm) resulted in lethal effects of these two gases that were additive. In contrast, coexposure to hydrogen cyanide and 5% carbon dioxide (not lethal by itself) resulted in an increase in lethality of hydrogen cyanide, reflected as a decrease of the hydrogen cyanide LCs, value to 75 ppm. The toxicity of pure hydrogen cyanide gas in monkeys was compared with hydrogen cyanide-containing atmospheres generated by pyrolyzing polyacrylonitrile (PAN) (Purser et al. 1984). For a given chamber hydrogen cyanide concentration, the smoke atmospheres generated from pyrolyzed PAN, which also contained other nitriles as well as carbon monoxide, were less toxic than hydrogen cyanide gas alone, both in terms of time to incapacitation and the severity of clinical signs. This discovery was surprising since it was expected that the presence of organic nitriles such as acetonitrile, benzonitrile, and unreacted acrylonitrile, although less toxic than hydrogen cyanide on a molar basis, would produce an additive effect. In addition, the presence of relatively high concentrations of carbon monoxide in the PAN atmospheres should also have increased the toxicity. From these studies, the authors suggested that when death occurs in humans following fires, the initial rapid incapacitation 53 2. HEALTH EFFECTS may be caused by cyanide; whereas, sometime later, the actual cause of death may be carbon monoxide poisoning. Addition of sodium cyanide (5 mM) and tributyltin (10 pM) to human erythrocyte suspensions resulted in a synergistic increase in tributyltin-induced hemolysis (Gray et al. 1986). Mechanisms are not clear, but may involve elevated pH of high sodium cyanide concentrations. Synergism has also been observed between cyanide and ascorbic acid. Guinea pigs exhibited increased toxic effects when treated with ascorbic acid prior to the oral administration of potassium cyanide (Basu 1983). When guinea pigs were treated solely with potassium cyanide, 38% exhibited slight tremors, whereas 100% of those treated with ascorbic acid and potassium cyanide exhibited severe tremors, ataxia, muscle twitches, paralysis, and convulsions. It has been suggested that this synergistic effect results from the ability of ascorbic acid to compete with cyanide for cystine, thus diminishing the detoxication of cyanide. Antidotes for cyanide have been intensively studied and reviewed (Way 1984). Cyanide antagonists can be classified into two general groups: those that act as sulfur donors for rhodanese-catalyzed cyanide detoxification and those that induce chemical binding of cyanide. Sulfur donors include sodium thiosulfate, polythionates, and thiosulfates. Sodium thiosulfate has been successfully used as an antidote against cyanide poisoning in humans for decades (Way 1984). A pharmacokinetic study in dogs demonstrated that intravenous administration of thiosulfate increased the detoxification rate of intravenously given cyanide to thiocyanate over 30 times (Sylvester et al. 1983). Pretreatment with thiosulfate decreased the biological half-life of cyanide from =39 minutes to =~15 minutes and also decreased the volume of distribution of cyanide from 498 mL/kg to 204 mL/kg. Thiosulfate pretreatment had prophylactic effects in guinea pigs exposed to cyanide by intravenous infusion (Mengel et al. 1989). The protection lasted for several hours depending on the dose of thiosulfate administered. Antagonists that induce the chemical binding of cyanide include sodium nitrite, amyl nitrite, and hydroxylamine. These compounds generate methemoglobin, which competes with cytochrome oxidase for cyanide-forming cyanmethemoglobin (Way 1984). Sodium nitrite has been effectively used in the therapy of cyanide intoxication in humans especially in combination with sodium thiosulfate (Way 1984). Studies in mice demonstrated that intraperitoneal pretreatment with sodium nitrite increased the LDy, value of intraperitoneally administered sodium cyanide from 3.18 to 7.95 mg CN/kg (Kruszyna et al. 1982). Peak methemoglobinemia was 35% at 40 minutes. Other methemoglobin generating agents seemed to be less effective. 4-Dimethylaminopropiophenol enhanced the LD, value to 6.36 mg CN/kg and hydroxylamine to 4.66 mg CN'/kg with peak methemoglobinemia being 40% and 36%, respectively at 7 minutes. The data suggested that sodium nitrite, a slow methemoglobin former, gave prolonged protection against cyanide, while animals treated with fast methemoglobin formers died later on, probably due to the cyanide release from the cyanmethemoglobin pool. An improvement of cyanide-altered cerebral blood flow was observed in dogs treated with sodium nitrite or 4-dimethylaminophenol following intravenous injection of hydrogen cyanide (Klimmek et al. 1983). Cobalt-containing compounds may also function as binders by forming a stable complex with cyanide. A dramatic antagonism of the lethal effects of potassium cyanide was reported when cobaltous chloride was administered to mice along with sodium thiosulfate (Isom and Way 1974a). The authors suggested that this synergistic antidotal effect of cobaltous chloride may be associated with the physiological disposition of the cobaltous ion and its ability to chelate both thiocyanate and cyanide ions. This ability is also utilized when (dicobalt ethylenediamine tetraacetate acid (Co,EDTA) is used as a cyanide antidote. An improvement of cerebral aerobic metabolism and blood flow was observed in dogs treated with 10 mg/kg Co,EDTA intravenously following intravenous application of 1.6 mg CN/kg as potassium cyanide (Klimmek et al. 1983). The interaction with hydroxocobalamin (see Section 2.3.3) was also proposed as a mechanism for cyanide detoxification in cases 54 2. HEALTH EFFECTS of acute poisoning. It was demonstrated that intravenous administration of hydroxocobalamin (50-250 mg/kg) prior to or after intraperitoneal injection of potassium cyanide prevented lethality and decreased cyanide-induced toxic effects in mice (Mushett et al. 1952). Pretreatment of rats with chlorpromazine (10 mg/kg intramuscularly) and sodium thiosulfate (1,000 mg/kg intraperitoneally) greatly decreased or abolished the increase in plasma creatine kinase observed in rats exposed to hydrogen cyanide at 200 ppm for 12.5 minutes (O’Flaherty and Thomas 1982). In an in_vitro study, chlorpromazine and 4,4’-diisothiocyano-2,2’-stilbene disulfonic acid reduced cyanide-induced contractions in vascular smooth muscle (Robinson et al. 1985a). It was suggested that chlorpromazine prevents cyanide-induced calcium influx and reduces peroxidation of membrane lipids (Maduh et al. 1988). The ability of cyanide to combine with carbonyl groups of some intermediary metabolites (e.g., sodium pyruvate, o-ketoglutarate) to form cyanohydrin has been used for antidotal purposes. Pretreatment of mice with 1 g/kg sodium pyruvate intraperitoneally prior to subcutaneous injection of potassium cyanide caused an increase in the LDs, values from 3.1 to 5 mg CN'/kg (Schwarz et al. 1979). Sodium pyruvate also prevented the development of convulsions in cyanide-exposed mice. Similarly, intraperitoneal pretreatment of mice with 2 g/kg o-ketoglutarate before the intraperitoneal injection of potassium cyanide increased the LDs, value from 2.68 to 13.32 mg CN'/kg (Moore et al. 1986). It was further demonstrated that both sodium pyruvate and o-ketoglutarate enhanced the antidotal effects of other cyanide antagonists (e.g., sodium thiosulfate, sodium nitrite) (Moore et al. 1986; Schwarz et al. 1979). Several papers discuss the effects of oxygen alone or with other compounds on cyanide toxicity. Oxygen alone results in minimal antagonism in mice injected with potassium cyanide and only slightly enhances the antagonistic effects of sodium nitrite (Sheehy and Way 1968). The antidotal effect of sodium thiosulfate alone or in combination with sodium nitrite, however, was strongly enhanced by oxygen. Oxygen-treated mice did not show behavioral signs of cyanide intoxication below doses of 2.4 mg CN/kg as potassium cyanide; whereas air-treated animals showed effects such as gasping, irregular breathing, and convulsions at levels as low as 1.2 mg CN/kg as potassium cyanide (Isom et al. 1982). When mice were pretreated with sodium nitrite and sodium thiosulfate and either air or oxygen, the dose of potassium cyanide needed to cause a 59% inhibition of brain cytochrome oxidase more than doubled in mice in an oxygen atmosphere; all points on the oxygen curve differed significantly from the air-treatment curve. A striking enhancement of the oxidation of glucose to carbon dioxide was observed when oxygen, sodium nitrite, and sodium thiosulfate were given to mice dosed at 18 mg CN7/kg as potassium cyanide; no enhancement was noticed at 4 or 6 mg CN'/kg as potassium cyanide (Isom and Way 1974b). These studies indicate that oxygen can be used in supporting classical cyanide antagonists in the therapy of cyanide poisoning. The mechanism of the action is not known, since cyanide inhibits the cellular utilization of oxygen through inhibiting cytochrome oxidase, and, theoretically, the administration of oxygen should have no effect or useful purpose. 2.7 POPULATIONS THAT ARE UNUSUALLY SUSCEPTIBLE A susceptible population will exhibit a different or enhanced response to cyanide than will most persons exposed to the same level of cyanide in the environment. Reasons include genetic make-up, developmental stage, health and nutritional status, and chemical exposure history. These parameters result in decreased function of the detoxification and excretory processes (mainly hepatic and renal) or the pre-existing compromised function of target organs. For these reasons we expect the elderly with declining organ function and the youngest of the population with immature and developing organs will generally be more vulnerable to toxic substances than 55 2. HEALTH EFFECTS healthy adults. Populations who are at greater risk due to their unusually high exposure are discussed in Section 5.6, "Populations With Potentially High Exposure." Persons with a metabolic disturbance in the conversion of cyanide to thiocyanate may be at greater risk. A defect in the rhodanese system and vitamin B,, deficiency have been associated with tobacco amblyopia and Leber’s hereditary optic atrophy in persons exposed to cyanide in tobacco smoke (Wilson 1983). A number of dietary deficiencies may increase the risk of deleterious cyanide effects. Iodine deficiency, along with excess exposure to cyanide, may be involved in the etiology of such thyroid disorders as goiter and cretinism (Delange and Ermans 1971; Ermans et al. 1972). Protein deficiencies and vitamin B,, and riboflavin deficiencies may subject people in the tropics who eat cassava to increased risks of tropical neuropathies (Makene and Wilson 1972; Osuntokun 1972; Osuntokun et al. 1969). Furthermore, children and women seem to be more susceptible to the endemic spastic paraparesis in the cassava-consumption regions (Rosling 1987). Studies that have uncovered more severe effects in nutritionally deprived animals (Kreutler et al. 1978; Philbrick et al. 1979; Rutkowski et al. 1985) provide support to the observations in humans. In areas where cassava is a staple food, congenital hypothyroidism is present in 15% of newborns (Ermans et al. 1980), indicating that fetuses may be at a higher risk. Animal studies provide further evidence that fetuses may be at a higher risk than the general population. Teratogenic effects have been observed in rodents following inhalation, oral, and parenteral exposure to cyanide-containing compounds (Doherty et al. 1982, 1983; Singh 1981; Willhite 1982). An additional group of people who may be at greater risk are those who are exposed to cyanide but are unable to smell the chemical (Kirk and Stenhouse 1953). Patients with motor neuron disease (amyotrophic lateral sclerosis) possess a disorder in cyanide metabolism that may result in their higher susceptibility to cyanide (Kato et al. 1985). 2.8 METHODS FOR REDUCING TOXIC EFFECTS This section will describe clinical practice and research concerning methods for reducing toxic effects of exposure to cyanide. However, because some of the treatments discussed may be experimental and unproven, this section should not be used as a guide for treatment of exposures to cyanide. When specific exposures have occurred, poison control centers and medical toxicologists should be consulted for medical advice. 2.8.1 Reducing Peak Absorption Following Exposure Human exposure to cyanide may occur by inhalation, ingestion, or by dermal contact, but the general population is more likely to be exposed by inhaling air or ingesting food or water contaminated with cyanide. General recommendations for reducing absorption of cyanide include removing the exposed individual from the contaminated area and removing the contaminated clothing (Ellenhorn and Barceloux 1988; Goldfrank et al. 1990; Stutz and Janusz 1988). If the eyes and skin were exposed, they are flushed with water. However, in order not to become secondary victims, the rescuers may enter potentially contaminated areas only with self-contained breathing apparatus and protective clothing. Speed is essential during a rescue operation. In general, following oral exposure, emesis is contraindicated, but may depend on the situation. In order to reduce absorption of ingested cyanide, gastric lavage may be performed immediately after ingestion. Activated charcoal administration with a cathartic has been recommended. Individuals exposed by any route are commonly administered 100% oxygen and assisted ventilation including endotracheal intubation as needed. Hyperbaric oxygen has been advocated when patients do no respond to standard therapy (Litovitz et al. 1983). An antidotal combination of 56 2. HEALTH EFFECTS inhaled amyl nitrate and intravenous sodium nitrite and sodium thiosulfate are often indicated. Monitoring for metabolic acidosis, cardiac dysrhythmias, and possible pulmonary edema is suggested. 2.8.2 Reducing Body Burden The primary target for cyanide toxicity is the central nervous system following both the acute and chronic exposure. In addition, chronic exposure to low doses of cyanide causes hypofunction of the thyroid gland. Exposure to high doses of cyanide can rapidly lead to death (see Section 2.2). Cyanide is not stored in the organism and one available study indicates that >50% of the received dose can be eliminated within 24 hours (Okoh 1983). However, because of the rapid toxic action of cyanide, development of methods that would enhance metabolism and elimination of cyanide is warranted. Cyanide is metabolized in the body by two metabolic pathways that have been identified (Ansell and Lewis 1970). The first and major metabolic pathway involves the transfer of sulfane sulfurs from a donor to cyanide to yield thiocyanate (see Section 2.3). The reaction employs the enzyme rhodanese as a catalyst. Thiocyanate is a fairly stable compound and is excreted predominately in urine. Serum proteins (especially albumin) are a major internal pool of sulfane sulfurs. Their protective role against cyanide toxicity was confirmed in tests with laboratory animals (Rutkowski et al. 1985; Tewe and Maner 1980, 1982). In humans, the development of neuropathies in those chronically exposed to cyanide in their cassava diet was attributed to the concurrent protein deficiency (Osuntokun 1968). A group of cyanide antagonists are sulfur donors that aid in the conversion of cyanide to thiocyanate. The major representative, commonly used in cases of cyanide poisoning, is sodium thiosulfate (Bonsall 1984; Mengel et al. 1989; Schubert and Brill 1968; Sylvester et al. 1983). Similarly, other sulfane sulfur donors have protective effects against cyanide toxicity. The second and minor metabolic pathway consists of the reaction of cyanide with cystine to yield cysteine and B-thiocyanoalanine (Wood and Cooley 1955). The latter is then converted to 2-imino-4-thiazolidinecarboxylic acid and excreted in urine. Cystine has not been used for the purpose of mitigation of cyanide effects because its contribution to detoxification via this pathway is minor. 2.8.3 Interfering with the Mechanism of Action for Toxic Effects The mechanism of cyanide toxicity is well understood (see Section 2.4). Cyanide inhibits the activity of various enzymes by binding to their metallic cofactors. By blocking the action of cytochrome oxidase, histotoxic hypoxia/anoxia develops rapidly in exposed organisms. The ability of cyanide to bind to metallic ions is utilized with antidotes that cause methemoglobinemia in exposed organisms. Cyanide binds to the ferric ion of methemoglobin to form inactive cyanmethemoglobin (see Section 2.6). Antidotes utilized for this purpose either clinically or experimentally include amyl nitrite, sodium nitrite, hydroxylamine, p-aminopropiophenone, and 4-dimethylaminophenol (Bright and Mars 1987; Kruszyna et al. 1982; Schubert and Brill 1968). The disadvantage of these antidotes is that the methemoglobinemia further aggravates the depletion of tissues from oxygen. Therefore, antidote-induced methemoglobin levels need to be closely followed in clinical practice. Although not without risk, this approach constitutes the only real clinical pathway to be followed. Cyanide’s binding to metallic ions is also employed in a reaction with cobalt-containing compounds that yields cyanocobalamin (see Section 2.6). Metallic cobalt is not used because of its toxicity; however, CO2EDTA (Klimmek et al. 1983) and hydroxocobalamin (Benabid et al. 1987; Mengel et al. 1989; Mushett et al. 1952) were effective as antidotes both in clinical and laboratory trials. Both of these antidotes have the advantage of not 57 2. HEALTH EFFECTS inducing methemoglobinemia. Similarly, cyanide was found to form stable complexes with selenite (Palmer and Olson 1979). It is possible that further research may develop other metal-containing compounds usable as cyanide antidotes. In an effort to find additional antidotes that would not produce methemoglobinemia, compounds such as sodium pyruvate, o-ketoglutarate, oxaloacetate, and pyridoxal 5’-phosphate have been introduced (see Section 2.6). Interactions of cyanide with carbonyl groups of these compounds lead to formation of inert cyanohydrin intermediates (Keniston et al. 1987; Moore et al. 1986; Schwartz et al. 1979; Yamamoto 1989). Their use has been, however, limited only to the potentiation of other antidotes. In addition, other chemicals such as a-adrenergic blocking agents like chlorpromazine (O'Flaherty and Thomas 1982; Way and Burrows 1976)) or oxygen (Sheehy and Way 1968) may be used to enhance the protective action of other antidotes. However, the mechanism of their action is not well understood. Further research for a potent and safe antidote to mitigate cyanide toxicity is desirable. It must be stressed, however, that the therapeutical value of the antidotes mentioned above is heavily dependent on the time lapse between intoxication and their use, since usual cyanide poisoning episodes are highly acute and proceed at very high speeds. 29 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of cyanide is available. Where adequate information is not available, ATSDR, in conjunction with the National Toxicology Program (NTP), is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of cyanide. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce or eliminate the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 2.9.1 Existing Information on Health Effects of Cyanide The existing data on health effects of inhalation, oral, and dermal exposure of humans and animals to cyanide are summarized in Figure 2-5. The purpose of this figure is to illustrate the existing information concerning the health effects of cyanide. Each dot in the figure indicates that one or more studies provide information associated with that particular effect. The dot does not imply anything about the quality of the study or studies. Gaps in this figure should not be interpreted as "data needs” information (i.c., data gaps that must necessarily be filled). In the section that follows, data needs are identified for cyanide forms for which toxicity data were available and were, therefore, summarized in Section 2.2. These forms include primarily sodium cyanide, potassium cyanide, and hydrogen cyanide. As seen from Figure 2-5, information is available regarding death, systemic effects of acute exposure, and neurological effects in humans after inhalation, oral, and dermal exposure to cyanide. In addition, information is available regarding chronic systemic effects in humans after inhalation and oral exposure. 58 2. HEALTH EFFECTS FIGURE 2-5. Existing Information on Health Effects of Cyanide SYSTEMIC @ &/ / & &° © S % s/e <& &° SS & o& & f s & SAR SESSA VE VE EVA Inhalation ® Oo ® ® Dermal oO ® HUMAN SYSTEMIC © &/ > & & & 3° F/ ® < S$ & / & S/S F/E/&/ J S/F) E/) F/ F Inhalation | ® | ® | ® ® Dermal ®| 0 ® ANIMAL @® Existing Studies F15105-6 59 2. HEALTH EFFECTS Data regarding death, systemic effects of acute exposure, and neurological effects were obtained for animals following inhalation, oral, and dermal exposure to cyanide. Furthermore, information was obtained regarding systemic effects after intermediate-duration inhalation and oral exposure, and chronic oral exposure. In addition, information exists regarding developmental and reproductive effects after oral exposure of animals to cyanide. 2.9.2 Identification of Data Needs Acute-Duration Exposure. The targets of acute cyanide exposure are the central nervous system, respiratory system, and cardiovascular system. Exposure to high levels of cyanide leads rapidly to death. Lethality data are available in humans for acute inhalation (Dudley et al. 1942; Singh et al. 1989), oral (Gettler and Baine 1938), and dermal (Rieders 1971) exposure to hydrogen cyanide; however, specific exposure levels are often not available. Lethality studies were performed in several animal species, and LCy, and LDy, values were derived for inhalation (hydrogen cyanide and cyanogen) (Ballantyne et al. 1983a), oral (potassium cyanide, sodium cyanide, and calcium cyanide) (Ballantyne 1983a, 1988), and dermal (hydrogen cyanide, potassium cyanide, and sodium cyanide) (Ballantyne 1983a, 1988) exposures. The most common systemic effects observed were dyspnea and palpitations. The effects were seen in humans regardless of route of cyanide exposure. Since most of the animal studies reported lethality as an end point, information regarding acute systemic effects in animals is limited and no suitable NOAEL values are available to serve as the basis for MRLs. Additional acute studies by all routes using several dose levels and examining comprehensive end points would help to determine thresholds for known targets and for any new target organs that might be identified. The information would be useful to populations living near hazardous waste sites that can be exposed to cyanide in contaminated water or soil for a short time. Intermediate-Duration Exposure. No intermediate-duration studies were located regarding cyanide effects in humans. A few inhalation (Valade 1952) and oral (Gerhart 1986, 1987; Jackson 1988; Philbrick et al. 1979; Tewe and Mauer 1981b) studies indicated that the target organs of intermediate-duration exposure to cyanide toxicity are the central nervous system (potassium cyanide, potassium-silver cyanide, cyanogen, copper cyanide, and hydrogen cyanide) and the thyroid gland (potassium cyanide). In addition, dermal hematological, and renal effects may be caused by oral exposure. No intermediate-duration dermal studies were available. It is known, however, that cyanides can rapidly penetrate the skin and similar toxic effects are presumed. The database for intermediate-duration exposure is insufficient to derive an MRL because some studies used a small number of animals, an insufficient description of effects, concentrations considered to be lethal to humans, and because of the observation of serious effects at the exposure concentrations studied. A 90-day oral exposure study that examined copper cyanide toxicity in rats, showed several effects attributable to copper rather than to cyanide (Gerhart 1986). Additional studies on copper cyanide and other cyanide compounds containing toxic metals, such as potassium silver cyanide, would be useful to determine the contribution of the metal to the toxicity of these compounds. Other intermediate-duration oral studies have failed to identify a NOAEL for neurological effects, the most sensitive end point. Therefore, an intermediate-duration oral MRL was not derived. Well-designed 90-day studies in animals by the inhalation, oral, and dermal routes would be useful for establishing dose-response relationships and identifying other possible targets. The information will be useful for people living near hazardous waste sites who may be exposed to low levels of cyanide for an intermediate-duration period of time. Chronic-Duration Exposure and Cancer. Some reports of occupationally exposed workers indicated that low concentrations of hydrogen cyanide may have caused neurological, respiratory, cardiovascular, and thyroid effects (Blanc et al. 1985; Chandra et al. 1980, 1988; El Ghawabi et al. 1975). The route of exposure was predominantly inhalation, although dermal exposure can also occur in the work place. The studies, however, lacked either information about exposure levels or used small cohorts of workers. Studies in populations that used cassava roots as a main source of their diet described the neurological and thyroid effects of cyanide 60 2. HEALTH EFFECTS consumption (Osuntokun 1972, 1980). For chronic exposure in animals, only one oral study in rats (hydrogen cyanide) was located (Howard and Hanzal 1955). However, the reliability of this study is low because of the unstable cyanide levels in their feed throughout the experiment due to evaporation of cyanide. Furthermore, no effects were found in the study besides nondose-related changes in weight gain in female rats, but not in male rats. No chronic studies in animals were located for the inhalation and dermal routes. Therefore, data are not sufficient to derive MRL values for chronic exposure. A chronic bioassay that examines long-term effects of low cyanide levels by the inhalation, oral, and dermal routes would be useful. This information is important to humans occupationally exposed or exposed to contaminated air, water, or soil at or near hazardous waste sites. No studies were located regarding carcinogenicity of cyanide in humans or animals. The results of the chronic bioassays suggested above may contribute some new insights. Genotoxicity. In vitro studies with cyanide in the form of potassium cyanide did not show any mutagenic activity in S. typhimurium or E. coli (De Flora 1981, 1984). One study suggested that hydrogen cyanide may be mutagenic (Kushi et al. 1983); the induction of reverse mutations was higher without metabolic activation. No genotoxicity was found in one in vivo study with potassium cyanide in mice (Friedman and Staub 1976). Considering that most of the genotoxicity studies have negative results and that there is a lack of carcinogenicity data, further genotoxicity studies may not be needed at this time. Reproductive Toxicity. No data were located regarding reproductive effects of cyanide in humans. One animal study reported increased resorptions in rats following oral exposure to a cassava diet (Singh 1981). Because some human populations use cassava roots as the main source of their diet, further information regarding this observation would be useful for these populations, but this is probably not a concern for people living in the United States. Increased gonadal weight was found in male rats in 90-day oral studies of copper cyanide and potassium silver cyanide (Gerhart 1986, 1987). Assuming similar toxicokinetics of cyanide following exposure by the inhalation, oral, and dermal routes, reproductive effects may be also expected after inhalation and dermal exposure. More studies by all three routes assessing reproductive function in animals after exposure to hydrogen cyanide, potassium cyanide, and sodium cyanide would be useful for the purpose of extrapolating the data to human exposure. Developmental Toxicity. No studies were located regarding developmental effects in humans exposed to cyanide by any route. Developmental studies in animals were performed only following oral exposure and contradicting results were obtained. Teratogenic effects of cyanide exposure were observed in rats and hamsters fed a cassava diet (Frakes et al. 1986; Singh 1981), while no effects were found in rats and pigs fed cassava diets alone or supplemented with potassium cyanide in other studies (Tewe and Maner 1981a, 1981b). Furthermore, growth retardation was the only effect in weanling rats in the second generation of the two- generation oral exposure study with potassium cyanide. More data regarding developmental toxicity in experimental animals would be useful to identify the possible risk for humans. Immunotoxicity. No data were located regarding immunological effects in humans or animals after inhalation or oral exposure to cyanide. A battery of immune function tests has not been performed in humans or animals but would be useful to clarify whether cyanide is an immunotoxin. Neurotoxicity. The central nervous system is an important target for cyanide toxicity in humans and animals following exposure by all three routes. Acute exposure to high levels of cyanide, regardless of the form, leads quickly to death that is preceded by dyspnea, convulsions, and central nervous system depression. Neurological and behavioral effects were observed in humans after chronic inhalation exposure to hydrogen cyanide in the workplace (Blanc et al. 1985; Chandra et al. 1988; El Ghawabi et al. 1975). Oral exposure to cyanide led to 61 2. HEALTH EFFECTS the development of severe peripheral neuropathies, and hearing and visual problems in those who used cassava as a staple in the diet (Osuntokun 1980). Experimental studies in animals exposed to hydrogen cyanide or cyanide compounds by inhalation (Purser et al. 1984; Valade 1952), oral (Philbrick et al. 1979), or dermal routes (Ballantyne 1983b), have found neurological effects similar to those seen in humans. Behavioral changes were reported in pigs after oral exposure to cyanide. Additional studies for neurological effects for all routes and durations would be useful for determining the NOAEL values for this most sensitive end point. Of particular value would be studies that try to correlate morphological changes, such as demyelination, with changes in higher functions, such as learning and memory. Epidemiological and Human Dosimetry Studies. Human exposure to low levels of cyanide is quite common. Cigarette and fire smoke contain cyanide (Fiksel et al. 1981); it is used as a postharvest fumigant (Jenks 1979) and can even be detected in drinking water supplies (Fiksel et al. 1981). Furthermore, workers are exposed to cyanide in several industries (Blanc et al. 1985). Although several studies reported neurological and thyroid effects in workers chronically exposed occupationally, dose relationships of these effects are not known, and the effects may have been confounded by simultaneous exposure to other chemicals. Similarly, exact correlations between environmental exposures and cyanide levels in blood or urine were not established. Therefore, occupational studies that would provide data on exposure levels and concentrations found in body fluids would be useful. These data might be useful for monitoring populations exposed to low levels of cyanide from contaminated waste sites. Furthermore, studies regarding the health status of such populations would be informative. Biomarkers of Exposure and Effect. Concentrations of cyanide and its metabolite thiocyanate can be measured in the blood, urine, and tissues (Way 1984). Since certain amounts of cyanide can always be found in the organism, only exposure to higher doses can be detected by this way. Cyanide is metabolized in the body to thiocyanate in a reaction that is catalyzed by an enzyme rhodanese and mercaptopyruvate sulfur transferase (Ansell and Lewis 1970). Rhodanese concentrations can be measured in tissues; however, this method is not routinely used. Studies to better quantitate cyanide exposure would be helpful. No biomarkers were identified that are useful for characterizing effects induced by exposure to cyanide. The target organs of cyanide toxicity are the central nervous system, the cardiovascular system, and the thyroid gland. However, exposure to other chemicals may have similar effects. More studies to identify subtle biochemical changes to serve as biomarkers of effects of cyanide exposure would be useful. Absorption, Distribution, Metabolism, and Excretion. Hydrogen cyanide, sodium cyanide, and potassium cyanide, are readily absorbed following inhalation, oral, and dermal exposures (Ballantyne 1983a). Inhalation exposure provides the most rapid route of entry. Cyanide is distributed throughout the body and detoxified by a mitochondrial enzyme, rhodanese (Ansell and Lewis 1970). Other detoxification pathways include spontaneous reaction with cysteine and the reaction with hydroxocobalamin. The severity and rapidity of the onset of effects depends on the route, dose, duration of exposure, and the cyanide compound administered. Once cyanides have been absorbed, excretion is similar in humans and animals. Cyanide metabolites are excreted primarily in urine, and small amounts of hydrogen cyanide are eliminated through the lungs (Farooqui and Ahmed 1982; Okoh 1983). Additional quantitative data on the toxicokinetics of cyanide would be useful, because there are few studies available that quantitate absorption and distribution. No data were found that dealt with saturation kinetics in cyanide metabolism. Comparative Toxicokinetics. Several studies on cyanide lethality and toxicity indicate that the central nervous system, the cardiovascular system, and the thyroid gland are the target organs in both humans and animals. Toxicokinetic studies have not been performed in humans; however, data regarding cyanide distribution have been 62 2. HEALTH EFFECTS obtained during autopsies in several lethal cases of poisoning following inhalation or oral exposure to hydrogen cyanide, sodium cyanide, or potassium cyanide (Fink 1969; Gettler and Baine 1938). Most of the toxicokinetic studies in animals were published between 1935 and 1965. As a result, much of the information is descriptive rather than quantitative, and the quantitative data presented were generated with inaccurate analytical equipment and methodologies. However, more recent studies in rats with hydrogen cyanide, sodium cyanide, and potassium cyanide indicate a pattern of distribution that is similar to that in humans (Ballantyne 1983a, 1983b; Buzaleh et al. 1989; Yamamoto et al. 1982). Furthermore, a study regarding transocular exposure showed that tissue concentrations of cyanide in rabbits varied depending on the cyanide compound used (Ballantyne 1983a, 1983b). Additional toxicokinetic data in several species would be needed to identify the best model for assessing human risk. Methods for Reducing Toxic Effects. The mechanism by which cyanide enters the blood stream in humans is not known; but due to the relative small size of the molecule, it is possible that cyanide simply follows a concentration gradient. Administration of activated charcoal has been recommended for reducing oral absorption (Ellenhorn and Barceloux 1988; Stutz and Janusz 1988). Identification of additional substances that could prevent or delay absorption and that do not represent a toxic risk per se would be valuable. Cyanide is not stored in the organism, but it has a rapid toxic action; the development of methods that would enhance metabolism and elimination, thus reducing body burden, would be useful. Further research aimed at identifying metal-containing compounds, other than selenite and cobalt compounds, usable as cyanide antidotes, would be valuable. 2.9.3 On-going Studies The National Toxicology Program reports that short term toxicity studies in rats and mice exposed to sodium cyanide in the drinking water are scheduled for peer review (NTP 1990). New possibilities for effective therapy of cyanide intoxication are being tested in several studies. Chemically modified rhodanese is being used in mice to evaluate its prophylactic and therapeutic effectiveness against cyanide poisoning in a study in progress (FEDRIP 1990). Several recent abstracts describe studies that have not yet been published. The mechanism of the antidotal effects of sodium tetrathionate was investigated in guinea pig liver homogenate (Baskin and Kirby 1990). The clinical response to therapy with the cyanide antidote (nitrite and thiosulfate) was surveyed in 17 cyanide-poisoned patients (Ger et al. 1988). Furthermore, the effectiveness of the standard cyanide antidote kit was reviewed in six patients treated for smoke inhalation (Kirk et al. 1989). The results of clinical case reports indicate that severe parkinsonism may develop in humans after acute oral cyanide poisoning (Kadushin et al. 1988). An epidemiology study suggests that there is an association between chronic lymphocytic leukemia and cyanide exposure (Malone et al. 1987). The age related increase in susceptibility to cyanide poisoning was reported in mice (McMahon and Birnbaum 1990). The results were supported by in vitro observation of lower rhodanese activity on aged animals. In order to reveal the mechanism of cyanide-induced injury, studies in vitro were performed on isolated hearts (species not specified) (Kopp et al. 1989) and isolated guinea pig livers (Alexander and Baskin 1987). 63 3. CHEMICAL AND PHYSICAL INFORMATION 3.1 CHEMICAL IDENTITY Data regarding the chemical identity of several cyanide compounds are reported in Table 3-1. 3.2 PHYSICAL AND CHEMICAL PROPERTIES The physical and chemical properties of selected cyanide compounds are presented in Table 3-2. Cyanides form strong complexes with many metals, particularly those of the transition series. One example of such complexation is the reaction of cyanide with iron in the formation of ferrocyanide and ferricyanide complexes. Solutions of ferrocyanides and ferricyanides can form hydrogen cyanide and cyanide ions when exposed to sunlight or ultraviolet radiation. Cyanogenic glycosides are cyanide compounds produced naturally in many plants. These glycosides produce hydrogen cyanide when hydrolyzed (Towill et al. 1978). TABLE 3-1. Chemical Identity of Cyanide and Compounds? Characteristic Hydrogen cyanide Sodium cyanide Potassium cyanide Calcium cyanide Synonym(s) Formonitrile; Cyanide of sodium; Cyanide of potassium; Calcid; calcyan; hydrocyanic acid; hydrocyanic acid, hydrocyanic acid, cyanide of calcium prussic acid sodium salt potassium salt Registered trade name(s) Cyclone B Cyanogran No data Caswell No. 142 Chemical formula HCN NaCN KCN Ca(CN), Chemical structure H-C=N Na*-C=N" K*-C=N" "‘N=C-Ca*2-C=N" Identification numbers: CAS registry 74-90-8 143-33-9 151-50-8 592-01-8 NIOSH RTECS MWe6825000 VZT530000 TS8750000 EW0700000 EPA hazardous waste P063, D003 P106, D003 P098, D003 P021 OHM/TADS 7216749 7216892 7216862 7216626 DOT/UN/NA/IMCO shipping UN1051; IMO 6.1 UN1689; IMO 6.1 UN1680; IMO 6.1 UN1575; IMO 6.1 HSDB 165 734 1245 242 NCI No data No data No data No data 3HSDB 1990 CAS = Chemical Abstracts Services; DOT/UN/NA/IMCO = Department of Transportation/United Nations/North America/Intemational Maritime Dangerous Goods Code; EPA = Environmental Protection Agency; HSDB = Hazardous Substances Data Bank: NCI = National Cancer Institute; NIOSH = National Institute for Occupational Safety and Health; OHM/TADS = Oil and Hazardous Materials/Technical Assistance Data System; RTECS = Registry of Toxic Effects of Chemical Substances NOILVWHOLNI TVYOISAHd ANV TVOINIHO '€ v9 TABLE 3-1 (Continued) Characteristic Copper(l) cyanide Potassium silver cyanide Cyanogen Cyanogen chloride Synonym(s) Cuprous cyanide, Potassium argentocyanide, Carbon nitride, Chlorine cyanide, cupricin potassium dicyanoargentate dicyanogen chlorocyan Registered trade name(s) Al3-28745 No data No data Caswell No. 267 Chemical formula CuCN KAg(CN), (CN), CNC Chemical structure Cu-C=N K*Ag(CN),I N=C-C=N Cl-C=N Identification numbers: CAS registry 544-92-3 506-61-6 460-19-5 506-77-4 NIOSH RTECS GL7150000 TT5775000 GT1925000 GT2275000 EPA hazardous waste P029 P099, D003, DO11 P031, D003 P033, D003 OHM/TADS No data No data 7216656 7216658 DOT/UN/NA/IMCO shipping UN1587; IMO 6.1 No data UN1026; IMO 2.3 UN1589; IMO 2.3 HSDB 1438 6053 2130 917 NCI No data No data No data No data NOLLYWHOINI TVOISAHd ANV TVOIN3HO ‘© S9 TABLE 3-2. Physical and Chemical Properties of Cyanide and Compounds? Property Hydrogen cyanide Sodium cyanide Potassium cyanide Calcium cyanide Molecular weight 27.032 49.02" 65.11" 92.122 Color Colorless? Whig] White] Colorless or white? Physical state Gas? Solid Solid Solid? Melting point, °C -13.249 563.72 634.59 Decomposes at >350°C2 Boiling point, °C 25.709 15002 No data No data Density, g/cm 0.6884 (liquid at 20°c)d 1.60 (for cubic)? 1.563 (for cubic)d 1.8-1.9 {commercial product) Odor Faint bitter almond odor® ~~ Odorless when dry, emits Faint bitter almond odor? Faint bitter almond odor” slight of HCN in damp air Odor threshold: Water 0.17 ppm (WN b No data No data No data Air 0.58 ppm (VV) No data No data No data Solubility: Water Miscible? 48 9/100 mL at 10°C® 71.6 g/100 mL at 25°c9 Soluble in water with gradual liberation of HCN" Organic solvent(s) Soluble in ethanol? Slightly soluble in Slightly sgluble in No data ethanol and formamide? ethanol Partition coefficients: Log Kay 0.66° -0.44° No data No data Log Ko No data d No data d No data No data Vapor pressure, mm Hg 264.3 (at 0°C) 0.76 at 800°C No data No data Henry's law constant 5.1x]0°2 atm-m3/molf No data No data No data Autoignition temperature,°C 538 No data No data No data Flashpoint, °C -17.8 (closed cup)? No data No data No data Flammability limits 6-41 vol % in air at 20°C No data No data No data Convergion factors: mg/m*® to ppm in air, 20°C ppm to mg/L in water ppm to mg/kg in soluble samples Explosive limits 1 mg/m® = 0.890 ppm ppm (WA) = mg/L = pg/mL ppm (Ww) = mg/kg = pg/ Upper, 40%; lower, 5.6% i ppm (WAN) = mg/L = pg/mL ppm (w/w) = mg/kg = ug/g No data i ppm (WA) = mg/L = pg/mL ppm (ww) = mg/kg = pg/g No data i ppm (WA) = mg/L = pg/mL ppm (ww) = mg/kg = pg/g No data 2Weast 1985 Amoore and Hautula 1983 CHawley 1981 Jenks 1979 ®EPA 1984 Yoo et al. 1986; value at 25°C and saturation pressure 9HSDB 1990 PWindholz 1983 'Since these compounds do not exist in the atmosphere in the vapor phase, their concentrations are always expressed in weight by volume unit (e.g., mg/m). ITowill et al. 1978 1984 HCN = hydrogen cyanide NOILVNHO4NI TVOISAHd ANV TVOINIHO ‘© 99 TABLE 3-2 (Continued) Property Potassium silver cyanide Cyanogen Cyanogen chloride Copper(l) cyanide Molecular weight 199.01" 52.042 61.48" 89.562 Color White" Colorless? Colorless® White? Physical state Solid Gas? Gas® Solid? Melting point, °C No data 27.92 6 473 (in No)? Boiling point, °C No data 21470 13.8" Decomposes? Density, g/cm 2.362 0.9537 at -21.17°C3 1.186" 2.922 Odor No data Almond-like odor Highly irritating” No data Odor threshold: Water No data No data No data No data Air No data No data No data No data Solubility: Water Soluble" Soluble? Soluble Insoluble? Organic solvent(s) Slightly soluble in Soluble in ethanol and Soluble in ethangl and No data ethanol? ethyl ether? and ethyl ethe Partition coefficients: Log Koy No data No data No data No data Log Koc No data No data . No data No data Vapor pressure, mm Hg No data 3,800 at 20°C) 760 at 13.8°Ch No data Henry's law constant No data No data No data No data Autoignition temperature No data No data No data No data Flashpoint No data No data No data No data Flammability limits No data 6-32% in air® No data No data Gonvergion factors: mg/m to ppm in air, 20°C ppm to mg/L in water ppm to mg/kg in soluble samples Explosive limits i ppm (WA) = mg/L = pg/mL ppm (ww) = mg/kg = pg/g No data 1 mg/m = 0.462 ppm ppm (WA) = mg/L = pg/mL ppm (WW) = mg/kg = Hag Upper, 32%; lower, 6.6% 1 mg/m = 0.391 ppm ppm (WA) = mg/L = pg/mL ppm (w/w) = mg/kg = pg/g No data i ppm (WA) = mg/L = pg/mL ppm (w/w) = mg/kg = ug/g No data NOILVWHO4NI TVOISAHd NV TTVOINIHO € 19 69 4. PRODUCTION, IMPORT, USE, AND DISPOSAL 41 PRODUCTION The demand for hydrogen cyanide in the United States during 1989 was 1.14 billion pounds; this demand is projected to grow at =3% per year to 1.30 billion pounds in 1994. Historically, the growth of the hydrogen cyanide demand had been 4.8% per year during the period of 1980-1989 (CMR 1990). Producers of hydrogen cyanide include: American Cyanamid, Fortier, Louisiana; BP Chemicals, Green Lake, Texas and Lima, Ohio; Ciba-Geigy, St. Gabriel, Louisiana; Degussa/Du Pont, Theodore, Alabama; Dow, Freeport, Texas; Du Pont, Beaumont, Texas, Memphis, Tennessee, Orange, Texas, and Victoria, Texas; Monsanto, Chocolate Bayou, Texas; Rohm and Haas, Deer Park, Texas; and Sterling, Texas City, Texas. The combined annual production capacity of these plants is 1.541 billion pounds (CMR 1990). As of January 1990, the following companies produced other cyanogen compounds in the United States (SRI 1990): cyanogen: Matheson Gas Products, Inc., Gloucester, Massachusetts; potassium cyanide: Du Pont, Memphis, Tennessee and W.R.Grace, Nashua, New Hampshire; and sodium cyanide: Dow, Freeport, Texas and Du Pont, Memphis, Tennessee and Texas City, Texas. Facilities in each state that manufactured or processed cyanide in 1988 and the range of the maximum amounts on site are shown in Table 4-1 (TRI88 1990). The Toxics Release Inventory (TRI) should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. There are two common methods of manufacturing hydrogen cyanide. The first results from the formation of hydrogen cyanide as a by-product during the synthesis of acrylonitrile from the reaction of propylene and ammonia with air. The second method results from direct synthesis by the reaction of methane and ammonia with air over platinum catalysts (CMR 1990; Jenks 1979). Of the total production capacity, the by-product of acrylonitrile production accounts for 20.5% of the hydrogen cyanide produced; direct synthesis accounts for the remaining 79.5% (CMR 1990). In recent years, the alkali cyanides have been manufactured by the neutralization or wet processes in which hydrogen cyanide reacts with alkaline hydroxide solutions (Jenks 1979). 4.2 IMPORT/EXPORT The imports and exports of hydrogen cyanide to and from the United States are negligible (CMR 1990). Approximately 5.76 million pounds of potassium cyanide, ferricyanide, and ferrocyanide and 23.1 million pounds of sodium cyanide were imported into the United States during 1984 through principal U.S. customs districts. Italy, Germany, and Great Britain were the primary exporters of cyanide chemicals to the United States (USDC 1985). Data regarding the export of cyanide salts from the United States were not located in the available literature. 43 USE The use pattern for hydrogen cyanide is the following: adiponitrile (for nylon 6/6), 43%; methyl methacrylate, 33%; sodium cyanide, 9%; cyanuric chloride, 6%; chelating agents, 5%; and miscellaneous uses, including methionine and nitriloacetic acid, 4% (CMR 1990). Miscellaneous applications also include the use of hydrogen cyanide as an insecticide and rodenticide for fumigating enclosed spaces (stored grain, etc.) and its use in the manufacture of ferrocyanides, acrylates, lactic acid, pharmaceuticals, and specialty chemicals (Jenks 1979; Worthing 1987). Cyanide salts have various uses. The most significant applications are used in electroplating and metal treatment, as an anticaking agent in road salts, and in gold and silver extraction from ores. Minor applications include use as insecticides and rodenticides, as chelating agents, and in the manufacture of dyes and pigments (Sax and Lewis 1987; Towill et al. 1978; Worthing 1987). In recent years, the use pattern of hydrogen 70 4. PRODUCTION, IMPORT, USE, AND DISPOSAL TABLE 4-1. Facilities That Manufacture or Process Cyanide® Range of maximum amounts on site Number of in thousands state? facilities of pounds Activities and usesd AL 9 0-999 1, 3,5,6,7, 8,13 AR 5 1-99 3,7, 8, 11, 12, 13 AZ 4 1-99 1, 7, 1 CA 33 0-99 1,2,3,6,8,9, 11, 12, 13 co 2 0.1-9 1, 1 cr 22 (1° 0.1-999 1,3, 4,7, 8,9, 10, 11, 12, 13 FL 3 0.1-0.9 6, 7, 12 GA 8 0.1-999 7, 11, 12, 13 ID 1 1-9 1 IL 51 (3)° 0-999 1,3,5,6,7, 8,9, 10, 11, 12, 13 IN 21 (2° 0-999 1, 4,5,6,7, 8,9, 11, 12, 13 KS 2 1-99 7,9, 12, 13 KY 10 0-99 1, 6, 7, 11, 12, 13 LA 6 1-9,999 1,3,4,5,6,7, 13 MA 7 1-999 7, 11, 12, MD 3 1-99 1, 3, 5, ME 2 1-9 9, 11 MI 28 (1° 0.1-99 1,2,3,4,6,7,8, 11, 12, 13 MN 9 (N° 0.1-99 1, 6, 11, 12, 13 MO 4 0.1-999 1,5,7, 1, 13 MS 6 (1° 0.1-99 5,7, 8, 11, 13 NC 4 (1° 1-99 11, 13 NE 2 0-9 1 NH 5 (1)° 10-9,999 1,3,4,5,7,9 1 NJ 9 (1° 0.1-999 1, 4, 5,6, 7,8,9, 10, 11, 13 NV 2 10-99 1 NY 17 (4)® 0.1-999 1,2,3,4,5,7,8, 11, 12, 13 OH 33 (1° 0-9,999 1,2,3,5,6,7,9, 11, 12, 13 oK 2 1-9 12, 1 OR 5 (1)® 0.1-9 1, 5, 12, 13 PA 22 0.1-49,999 1,2,3,5, 6,7, 8 11, 12, 13 PR 3 (Ne 0.1-999 6, 7,9, 12, 13 RI 6 0.1-999 2,3, 4, 8,12, 13 sC 7M 0-99 5, 7,8, 11, 12 ™ 8 0-9,999 1,2,3,4,5,7, 1, 12 © 26 0-49,999 1,2,3,4,5,6,7,9, 11, 12, 13 ut 1 0-0.09 1, 5 VA 5 0-99 9, 11, 12 WA 1 1-9 11, 12, 13 WI 1 0.1-99 7, 8,9, 12, 13 WV 3 0-9,999 1,5,6,7, 12 81R188 1990 Post office state abbreviations Cpata in TRI are maximum amounts on Activities/Uses: produce import for on-site use/processing for sale/distribution as a byproduct . as an impurity 2 7. as a reactant Number of facilities reporting "no the substance on site. 1. 2. 3. 4. 5. on site at each facility. 8. as a formulation component 9. as an article component 10. for repackaging only 11. as a chemical processing aid 12. as a manufacturing aid 13. ancillary or other use data" regarding maximum amount of 71 4. PRODUCTION, IMPORT, USE, AND DISPOSAL cyanide has slightly increased in favor of adiponitrile. For example, 38% of total hydrogen cyanide was used for adiponitrile manufacture in 1982, while the amount increased to 43% in 1989 (CMR 1982, 1990). 4.4 DISPOSAL Cyanide wastes usually undergo decontamination treatment prior to disposal. It has been estimated that 4,723 million gallons of cyanide-containing wastes are generated annually in the United States (Grosse 1986). Alkaline chlorination in the presence of sodium hydroxide or hypochlorite is the most widely used commercial method for treating cyanide-containing wastes. This method results in the conversion of the cyanide solution to the less toxic cyanate. Some other possible treatment techniques available include the following: large-scale outdoor burning following special precautions; ozonation; decontamination by treatment with caustic soda followed by addition to ferrous sulfate solution (nontoxic ferrocyanide forms); peroxidation to cyanate; electrolysis to carbon dioxide, ammonia, and cyanate; and biological decomposition to carbon dioxide and nitrogen. Formaldehyde in basic solution can convert free cyanide to substituted acetates. Copper and silver in electroplating wastes can be recovered as free metals with formaldehyde reduction. The complexes of zinc and cadmium can be recovered as the oxides with formaldehyde treatment. Calcium or sodium polysulfide treatment converts some cyanide wastes into less toxic thiocyanate. These examples suggest that typical treatments involve the decomposition of cyanides to less toxic compounds by physical or chemical processes. More than 97% of cyanide is typically removed from waste waters by alkaline chlorination, electrolysis, or ozonation process. Cyanide from some wastes can be removed by ion-exchange resins. After using an appropriate treatment method, cyanide wastes may be disposed of in a secured sanitary landfill (Grosse 1986; Higgins and Desher 1988; Tucker and Carson 1985). According to RCRA, cyanide-containing wastes are required to be treated by the best demonstrated available technology before the wastes can be disposed of in land. The concentration of cyanide permissible in wastes for land disposal vary according to the nature of wastes. For most wastes, with the exception of bottom stream from the acetonitrile column in the production of acrylonitrile, the maximum concentration in treated waste should not exceed 1.9 mg/L for total cyanides and 0.11 mg/L for cyanides amenable to chlorination (EPA 1989b). The possibility of disposal by injection of high-pH cyanide wastes into sandstone was investigated (Scrivner et al. 1986). It appears that the largest amount of cyanide waste is disposed of by underground injection (see Section 5.2) (TRI88 1990). 73 5. POTENTIAL FOR HUMAN EXPOSURE 5.1 OVERVIEW Anthropogenic sources are responsible for most of the cyanide in the environment. Cyanide also occurs naturally in the fruits, roots, and leaves of numerous plants. The major cyanide releases to water are discharges from metal finishing industries, iron and steel mills, and organic chemical industries (Fiksel et al. 1981). Effluents from the cyanidation process used in precious metal extraction contain high amounts of cyanide (Huiatt 1985; Scott 1985). The contribution of this source to the total cyanide discharge in water, however, is insignificant (Fiksel et al. 1981). Vehicle exhaust is the major source of cyanide released into the air (Fiksel et al. 1981). The major sources of simple and complex cyanide release to soil appear to be disposal of cyanide wastes in landfills and the use of cyanide-containing road salts. Cyanide has been identified in 390 of the 1,300 hazardous waste sites that have been proposed for inclusion on the NPL (HAZDAT 1992). The frequency of these sites within the United States can be seen in Figure 5-1. Cyanide is released into air mainly as hydrogen cyanide gas and, to a lesser extent, as particulate cyanides. Hydrogen cyanide can potentially be transported over long distances before reacting with photochemically generated hydroxyl radicals. The residence time of hydrogen cyanide in the troposphere has been estimated to be 1.4-4.3 years (Cicerone and Zellner 1983). Neither photolysis nor deposition by rainwater is expected to be a significant removal mechanism. Only 2% of the tropospheric hydrogen cyanide is expected to be transported to the stratosphere (Cicerone and Zellner 1983). In water, cyanide occurs most commonly as hydrogen cyanide. Hydrogen cyanide is expected to be removed from water primarily by volatilization. At low concentrations, some hydrogen cyanide may also be removed by aerobic or anaerobic biodegradation (Callahan et al. 1979). At soil surfaces, volatilization of hydrogen cyanide is a significant loss mechanism for cyanides. In subsurface soil, cyanide at low concentrations would probably biodegrade under both aerobic and anaerobic conditions. In cases where cyanide levels are toxic to microorganisms (i.e., landfills, spills), water-soluble cyanides may leach into groundwater. Despite the various ways cyanide is thought to be released into the environment, available monitoring data are limited. It appears that the general population may be exposed to cyanide by inhalation of contaminated air, ingestion of contaminated drinking water, and consumption of foods that contain cyanides. The concentration of cyanide in the northern hemisphere’s nonurban troposphere ranges from 160 to 166 ppt (ppt = parts per trillion) (Cicerone and Zellner 1983; Jaramillo et al. 1989). The mean cyanide concentration in most surface waters is not >3.5 pg/L (Fiksel et al. 1981). Cyanogen chloride is formed as drinking water is chlorinated (Jacangelo et al. 1989). The cyanogen chloride concentration in drinking water is 0.45-0.80 pg/L (Krasner et al. 1989). The cyanide content in certain varieties of lima beans can be as high as 3 mg/g (Honig et al. 1983), although values between 0.10 and 0.17 mg/g are common in U.S. lima beans (Towill et al. 1978). Due to the lack of data on cyanide content in total diet samples, the average daily intake could not be estimated. The National Occupational Exposure Survey (NOES) conducted by the National Institute for Occupational Safety and Health (NIOSH) estimated the number of workers who are potentially exposed to cyanides. Workers in various occupations may be exposed to cyanides, including workers involved in electroplating, metallurgy, pesticide application, firefighting, steel manufacturing, gas works operations, and metal cleaning (Fiksel et al. 1981). Exposure occurs primarily through inhalation and, less frequently, by skin absorption. Among the general population, subpopulations with the potential of exposure to cyanide at concentrations higher than background levels include cigarette smokers and nonsmokers who inhale secondary smoke, residents who live near industrial sites releasing cyanides to the environment, residents who live near cyanide-containing hazardous waste sites, and people who consume foods high in cyanogenic glycosides. FIGURE 5-1. FREQUENCY OF NPL SITES WITH CYANIDE CONTAMINATION * 3HNSOdX3 NVINNH HOH TVILN3LOd 'S FREQUENCY HHHFH 1 TO 4 SITES EH 5 TO 9 SITES 12 TO 19 SITES BE -< TO 30 SITES Derived from HAZDAT 1992 vL 75 5. POTENTIAL FOR HUMAN EXPOSURE 5.2 RELEASES TO THE ENVIRONMENT 5.2.1 Air Cyanide emissions into the air have been conservatively estimated at 44 million pounds/year based on data obtained during the middle to late 1970s. Over 90% of these emissions are attributed to releases from automobile exhaust. The second largest source of cyanide emission to the air results from the manufacture of methyl methacrylate, acrylonitrile, and hydrogen cyanide (Fiksel et al. 1981). More recent quantitative data regarding total cyanide emissions were not located in the available literature. Other smaller sources of cyanide release include emissions from iron and steel production, coal combustion (Fiksel et al. 1981), petroleum refineries (Fiksel et al. 1981), oil shale retorting processes (Hargis et al. 1986; Sklarew and Hayes 1984), municipal solid waste incinerators (Carotti and Kaiser 1972; Greim 1990), the combustion of acrylonitriles or other nitrogen-containing plastics (Brandt-Rauf et al. 1988; Fiksel et al. 1981), cigarette smoke (Fiksel et al. 1981), volatilization from cyanide waste disposed of in landfills, and direct release to the atmosphere from certain agricultural pest control activities (Fiksel et al. 1981). In 1976, an estimated 137,000 pounds of cyanide was released in the air from agricultural pest control, 18,000-180,000 pounds from incineration, and 13,000-750,000 pounds from cigarette smoke (Fiksel et al. 1981). The production of coke or other coal carbonization processes also release hydrogen cyanide into the atmosphere (Cicerone and Zellner 1983). Hydrogen cyanide is also released into the atmosphere from natural biogenic processes from higher plants, bacteria, and fungi. However, an estimate of the amount of hydrogen cyanide released from natural biogenic sources is not available (Cicerone and Zellner 1983). The amount of cyanide released to the atmosphere in 1988 by U.S. industrial facilities sorted by state is given in Table 5-1 (TRI88 1990). The TRI data should be used with caution since only certain types of facilities are required to report. This is not an exhaustive list. 5.2.2 Water There are numerous sources that release cyanide into water. Cyanide is released into water from both point and nonpoint sources. The major point sources of cyanide released to water are discharges from publicly owned treatment works (POTWs), iron and steel production, and organic chemical industries (Fiksel et al. 1981). Estimates based on data from the middle to late 1970s indicate that these sources account for =89% of the estimated 31 million pounds of total cyanide discharged annually to surface waters. Since metal finishing and organic chemical industries are estimated to account for 90% of the influent to POTWs, they are the dominant sources of both direct and indirect discharge of cyanide to water (Fiksel et al. 1981). The amount of cyanide released to surface water and POTWs in 1988 by U.S. industrial facilities sorted by state is shown in Table 5-1 (TRI88 1990). Based on the data in Table 5-1, the industrial discharge of cyanides into surface water and POTWs has decreased substantially in 1988 in comparison to the estimated discharge during the 1970s. The TRI data should be used with caution since only certain facilities are required to report. This is not an exhaustive list. The effluents from the cyanidation process used in the extraction of precious metals from their ores may contain high levels of cyanide (Huiatt 1985; Scott 1985). The total cyanide content of typical tailing pond effluents from gold mill tailing ponds may range from 0.3 to 61 mg/L (Scott 1985). However, the contribution from this source to the total discharge of cyanide has been estimated to be negligible (Fiksel et al. 1981). Leachates from solid waste disposal sites are point sources of cyanide release to groundwater (Myers 1983; Venkataramani et al. 1984). No quantitative estimate of the amount of cyanide entering the groundwater from this point source was located. As of July 12, 1989, the Contract Laboratory Program (CLP) Statistical Database reported detection of cyanide in 9.2% of the surface water samples near hazardous waste sites at a geometric mean concentration of 10 pg/L. It was estimated to occur in 17% of the groundwater samples from hazardous waste sites at a geometric mean concentration of 26.7 pg/L (CLPSD 1989). Note that the information used from the CLP Statistical Database includes data from NPL sites only. 1es ironment from Facili That Manufacture or Process Cyanide Releases to the Env TABLE 5-1. b Range of reported amounts released in thousands of pounds off-site waste transfer POTW transfer d Underground Total Air injection Water Land Environment Number of state® facilities 76 5. POTENTIAL FOR HUMAN EXPOSURE 3 ~ own am, oO 0 mM Nun . mgNnne ~ . ed c= wn ‘8 non oN 0 © %o oN MON . No« clRT N= ANC SMe cRnNonNTnNTNOO 565500 uEMEENEEEOMEE60000066EMME00 m o o °c co Menem eOMmM eM QmmaZmmm Nm ownMmmMmomMmm . . ER] . . JL [ 56555 0MEMEEE0556-E8000000000ME600 oc oc oc o ~ . 8 3 nin - Le] om. mM Fn Minino Smineom nomme Mm . . Moo lao 2 lg 39% «ON NSSRocw-rcllcR-nRereTods Cos cono . . ’ co oc o co o 0 M — Mm ~N Mmm wn on Mm Mmm "Mm o SC0C00000000000M000T0C0C300300800 1 [RC EEA OEEEAEEEEL0000555000000000 ~ oS -— Mm «© Lg] 0 Meine MM am Mm - . sl + sos oN «ON NSo0C0c0c0cNcccc0Necec8083303INochoo COCO OOOOOOOOOOOOOOO0O0000000000000 o o o o ~ «© RB cocoRocococococoloocococooooococoloncoe ' Coo SEES EEE EEEEE00050500000066600 [Yall all Tal wn am wn JNM mM = 0 MaNMMNMNO mM «so Mow © te .s Ms ON . ' ' ' ri 0-555 -EMEEE0000NdE00006666666600 oc o °c CNIMNNMO=eNOOMINROITININONLRNINNMD mM no Lal oN TABLE 5-1 (Continued) Range of reported amounts b released in thousands of pounds off-site Number of Underground Total d POTW waste state® facilities Air injection Water Land Environment transfer transfer SC 7 0-62.5 0-0 0-0.3 0-0 0.1-62.5 0-0.3 0-24.3 ™ 8 0-20 0-0 0-0.3 0-0.1 0-20 0-29 0-1.7 TX 26 0-691 0-2,410 0-8.5 0-51 0-2,461 0-110 0-1,468 ut 1 82-82 0-0 0-0 0-0 82-82 0-0 0.1-0.1 VA 5 0-10 0-0 0-0.1 0-0 0-10 0-0.3 0-1 WA 1 0.1-0.1 0-0 0-0 0-0 0.1-0.1 0.1-0.1 0.1-0.1 Wi 1 0-0.8 0-0 0-0.1 0-25 0-25.5 0-3.4 0-61.7 wv 3 0-241 0-0 0-1 0-0 1-241 0-0 0-0.8 21R188 (1990) ata in TRI are maximum amounts released by each facility. Quantities reported here have been rounded to the nearest hundred pounds, except those quantities > 1 million pounds which have been rounded to the nearest thousand pounds. Post office state abbreviation used The sum of all releases of the chemical to air, land, water, and underground injection wells by a given facility. Cc POTW = Publicly owned treatment works 3HNSOdX3 NVWNH HOH TVILNILOd 'S LL 78 5. POTENTIAL FOR HUMAN EXPOSURE The nonpoint sources of cyanide released to water are comprised of agricultural and road runoff and atmospheric fallout and washout. It has been estimated that a maximum of =2 million pounds of sodium ferrocyanide that are used as an anticaking agent in road salts during the winter in the northeastern United States are washed off from roads into streams and storm sewers (Cole et al. 1984; Fiksel et al. 1981; Gaffney et al. 1987). 5.2.3 Sail Estimates of amounts of cyanide released to soil from anthropogenic sources were not located. The largest anthropogenic sources of cyanide releases to soil probably result from the disposal of cyanide wastes in landfills and the use of cyanide-containing road salts. The amount of cyanide released to land by U.S. industrial facilities sorted by state is shown in Table 5-1 (TRI88 1990). Based on data in Table 5-1, only relatively small amounts of cyanides were discharged in hazardous waste sites from U.S. industrial facilities in 1988. However, some of cyanide wastes transferred off-site (see Table 5-1) may be ultimately disposed of in land after treatment and volume reduction. The TRI data should be used with caution since only certain facilities are required to report. This is not an exhaustive list. Natural biogenic processes (e.g., sorghum and other plants) also release cyanide into the soil. According to CLP Statistical Database, cyanide is estimated to occur at 8.5% of soils in the hazardous waste sites evaluated at a geometric mean concentration of 1236.8 pg/kg (CLPSD 1989). Note that the information used from the CLP Statistical Database includes data from NPL sites only. 5.3 ENVIRONMENTAL FATE 5.3.1 Transport and Partitioning Because hydrogen cyanide is a gas and has a relatively slow degradation rate in air (see Section 5.3.2), the atmosphere will be the ultimate sink for this compound. Cyanide has the potential to be transported over long distances from its emission source. Despite higher water solubility at saturated pressure, the removal of hydrogen cyanide by rainwater appears to be a negligible pathway (Cicerone and Zellner 1983). Since hydrogen cyanide is a gas, the removal by dry deposition is also likely to be negligible. However, metal cyanide particles, particularly water-soluble cyanide particles, are expected to be removed from the air by both wet and dry deposition. On the basis of Henry's law constant (see Table 3-2) and the volatility characteristics associated with various ranges of Henry’s law constant (Thomas 1982), volatilization is a significant and possibly dominant fate process for hydrogen cyanide in water. At a pH <9.2, most of the free cyanide in solution should exist as hydrogen cyanide, a volatile cyanide form (Towill et al. 1978). Variations in the volatilization rate are expected because this process is affected by several parameters including temperature, pH, wind speed, and cyanide concentration (Callahan et al. 1979). In a biodegradation study, the volatilization half-life of cyanide in river water kept in biochemical oxygen demand bottles (without bubbling air) at pH 7.4 was =10 days (Ludzack et al. 1951). When the bottles were aerated (rate of aeration not given), the volatilization half-life was only 14 hours. The volatilization rate was pH-dependent, with the rate faster at a lower pH. Data indicated that volatilization is a more important fate process than cyanide loss due to chemical and biodegradation reactions (see Section 5.3.2) (Ludzack et al. 1951; Raef et al. 1977). Additional data are necessary to assess the significance of cyanide sorption to suspended solids and sediments in water. The existing data indicate that the adsorption of hydrogen cyanide to suspended solids and sediment will not be significant. However, soluble metal cyanides may show stronger adsorption than hydrogen cyanide. The extent of adsorption increases with decreasing pH and increases with increasing iron oxide, clay, and organic 79 5. POTENTIAL FOR HUMAN EXPOSURE material contents of water. Adsorption is probably insignificant even for metal cyanides when compared to volatilization and biodegradation (Callahan et al. 1979). The simple metal cyanides and hydrogen cyanide do not bioconcentrate in aquatic organisms (Callahan et al. 1979; EPA 1985a). However, fish from water with soluble silver and copper cyanide complexes had metal cyanides in their tissues. The bioconcentration factors for such compounds in fish tissues are not known (Callahan et al. 1979). There is no evidence of biomagnification of cyanides in the food chain (Towill et al. 1978). Volatilization of hydrogen cyanide would be a significant loss mechanism for cyanides from soil surfaces at a pH <9.2. Although cyanide has a low soil sorption capability (Callahan et al. 1979), it is usually not detected in groundwater probably because of fixation by trace metals through complexation or transformation by soil microorganisms (Towill et al. 1978). In soils where cyanide levels are high enough to be toxic to microorganisms (i.e., landfills, spills), this compound may leach into groundwater (EPA 1984). The possibility of cyanide leaching into groundwater under certain conditions is confirmed by the detection of cyanides in groundwater samples from solid waste sites. 5.3.2 Transformation and Degradation 5.3.2.1 Air Most cyanide in the atmosphere exists almost entirely as hydrogen cyanide gas, although small amounts of metal cyanides may be present as particulate matter in the air (EPA 1984). The most important reaction of hydrogen cyanide in air is the reaction with photochemically generated hydroxyl radicals (Cicerone and Zellnar 1983). Based on a reaction rate constant of 3x10™* cm>®/(molecule-sec) at 25°C (Fritz et al. 1982) and assuming a daily average hydroxyl radical concentration of 5x10° molecules/cm®, the residence time for the reaction of hydrogen cyanide vapor with hydroxyl radicals in the atmosphere is =2 years. The rate of hydroxyl radical reaction with hydrogen cyanide in the air depends on the altitude, and the rate of the reaction is at least an order of magnitude faster at lower altitudes (Cicerone and Zellner 1983). The estimated residence time of hydrogen cyanide in air at different tropospheric altitudes when reaction with hydroxyl radicals is assumed to be the sole transformation mechanism varies between 0.5 and 14.0 years. Based on a maximum tropospheric singlet oxygen (O 'D) concentration of 8x107%/cm?, the atmospheric residence time for hydrogen cyanide due to reaction with O 'D alone can be estimated to be =40,000 years (Cicerone and Zellner 1983). This reaction is, therefore, not an important transformation process in the troposphere. It may be important in the stratosphere where the concentration of singlet oxygen is much higher. It was also reported that the removal of tropospheric hydrogen cyanide by photolysis and by reaction with ozone is not important, and only 2% of tropospheric hydrogen cyanide is transferred to the stratosphere (Cicerone and Zellner 1983). 5.3.2.2 Water Cyanide occurs most commonly as hydrogen cyanide in water, although it can also occur as the cyanide ion, alkali metal cyanides (e.g., potassium cyanide, sodium cyanide), relatively stable metallocyanide complexes (e.g., ferricyanide complex [Fe(CN)o]), moderately stable metallocyanide complexes (e.g., copper cyanide), or easily decomposable metallocyanide complexes (i.e., zinc cyanide [Zn(CN),]). The environmental fate of these cyanide compounds varies (Callahan et al., 1979). The alkali metal salts are very soluble in water. As a result, they readily dissociate into their respective anions and cations when released into water. Depending on the pH of the water, the resulting cyanide ion may then 80 5. POTENTIAL FOR HUMAN EXPOSURE form hydrogen cyanide or react with various metals in natural water. The proportion of hydrogen cyanide formed from soluble cyanides increases as the water pH decreases. At pH <7, >99% of the cyanide ions in water is converted to hydrogen cyanide. As the pH increases, cyanide ions in the water may form complex metallocyanides in the presence of excess cyanides; however, if metals are prevalent, simple metal cyanides are formed. In clear water or at water surfaces, some metallocyanides, such as ferrocyanides and ferricyanides, may decompose to the cyanide ion by photodissociation and subsequently form hydrogen cyanide. Hydrogen cyanide itself is not expected to undergo direct photolysis. The rate of free cyanide formation from the photolysis of ferrocyanide in runoff and surface water from wash out of ferrocyanide in deicing salt will be lower than cyanide formed from laboratory photolysis with clean water due to adsorption of ferrocyanide onto soil surfaces and sediment of surface waters, and light scattering in turbid waters in the field. The hydrolysis rates of hydrogen cyanide in acidic solution and the hydrolysis of cyanides under alkaline conditions are so slow that hydrolysis is not competitive with volatilization and biodegradation. Unlike water-soluble metal cyanides, insoluble metal cyanides are not expected to degrade to hydrogen cyanide (Callahan et al. 1979). Biodegradation is also a significant fate process in natural water systems. Although cyanide is toxic to microorganisms at concentrations <10 mg/L (Klecka et al. 1985; Malaney et al. 1959), acclimation appears to increase tolerance to this compound (Raef et al. 1977). A number of pure cultures of microorganisms degrade low concentrations of cyanide under both aerobic and anaerobic conditions (Callahan et al. 1979; Towill et al. 1978). Mixed microorganisms in sewage sludge or activated sludge acclimated to cyanide also significantly biodegrade concentrations <100 mg/L of most simple and complex cyanides (Gaudy et al. 1982; Pettet and Mills 1954; Richards and Shieh 1989; Shivaraman et al. 1985). The ferrocyanide complex was not easily biodegradable (Belly and Goodhue 1976; Pettet and Mills 1954). However, when an aqueous solution of potassium ferrocyanide was seeded with pure culture of Pseudomona aeruginosa, E. coli, or a mixture of the two bacteria, formation of free cyanide was observed after a delay period of =2 days (Cherryholmes et al. 1985). The rate of free cyanide formation increased with addition of nutrient in water, and a free cyanide concentration <4,000 pg/L was detected at the end of 25 days. It was shown that the free cyanide formation was due to biodegradation and not due to either photolysis or hydrolysis. The relevance of this study is difficult to assess because cyanide concentrations used in these experiments (3,300 mg/L) are rarely encountered in municipal and industrial discharges. Also, the relevance of using a pure culture for assessing biodegradation in natural waters is questionable since natural waters contain mixed cultures of bacteria. Under aerobic conditions, the biodegradation of free cyanide initially produces ammonia, which is converted to nitrate in the presence of nitrifying bacteria (Richards and Shieh 1989). Anaerobic biodegradation of cyanides under denitrification conditions produces nitrogen (Richards and Shieh 1989). The biodegradation half-life of cyanide at a concentration <6 mg/L in two natural river waters ranged from <10 to 24 days (Ludzack et al. 1951). 5.3.23 Soll By analogy to the fate of cyanides in water, it is predicted that the fate of cyanides in soil would be pH- dependent. Cyanide may occur as hydrogen cyanide, alkali metal salts, or as immobile metallocyanide complexes. In soil, cyanide present at low concentrations would biodegrade under aerobic conditions with the initial formation of ammonia, which will be converted to nitrate in the presence of nitrifying bacteria. Under anaerobic conditions, cyanides will denitrify to gaseous nitrogen. Cyanide ions in soil are not involved in oxidation-reduction reactions but may undergo complexation reactions with metal ions in soil (Towill et al. 1978). 81 5. POTENTIAL FOR HUMAN EXPOSURE 5.4 LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 5.4.1 Air The concentration of hydrogen cyanide in the northern hemisphere’s nonurban troposphere ranges from 160 to 166 ppt (v/v) (Cicerone and Zellner 1983; Jaramillo et al. 1989). Although ambient monitoring data regarding cyanide in air near source areas (e.g., hydrogen cyanide manufacturing industries, coke production industries, waste disposal sites) were not located in the available literature, the hydrogen cyanide concentration in the vicinity of the source areas is higher than the nonurban tropospheric concentration. The semiquantitatively measured hydrogen cyanide concentrations in the offgas from shale oil retorting processes ranged from 6 to 39 ppm (Sklarew and Hayes 1984). 5.4.2 Water Cyanide has been detected in waste waters from plating industries at a concentration <67,000 mg/L (Grosse 1986), in secondary effluent from a textile industry at a maximum concentration of 0.2 mg/L (Rawlings and Samfield 1979), and in the secondary effluent from a Los Angeles City waste water treatment plant at a concentration of 0.01 mg/L (Young 1978). In New York state alone, 47 industries discharged 3,877 pounds of cyanide into streams in 1982 (Rohmann 1985). Cyanide has also been found in groundwater below landfills and disposal sites (Anon 1989; Myers 1983; Venkataramani et al. 1984). A maximum concentration of 14.0 mg/L was reported in the leachate of one landfill with industrial wastes (Venkataramani et al. 1984). Data from the Nationwide Urban Runoff Program as of 1982 indicate that cyanide was found in 16% of the urban runoff samples collected in 19 cities across the United States. In samples where it was detected, the cyanide concentration ranged from 2 to 33 pg/L (Cole et al. 1984). Based on data obtained from the EPA STORET database, the mean cyanide concentration in most surface waters tested in the United States is not >3.5 pg/L (Fiksel et al. 1981); however, 37 of 50 states (74%) have locales where cyanide concentrations in ambient water are >3.5 pg/L. Areas with levels >200 pg/L include portions of southern California, North Dakota, South Dakota, Iowa, northwest Georgia, western New York, and western Pennsylvania (Fiksel et al. 1981). Cyanide at a concentration >1 pg/L was detected in water from the Great Lakes (Great Lakes Water Quality Board 1983). The concentrations of cyanide at various points of the Ohio River and its tributaries range from <5 to 80 pg/L. The highest concentration was detected in water from Beaver Falls, Pennsylvania (Ohio River Valley Sanitation Commission 1982). Cyanogen chloride is formed in drinking water due to reaction of humic substances with chloramine formed during chlorination (Ohya and Kanno 1987). It has been reported that the concentration of cyanogen chloride in drinking water is most influenced by the final disinfectant. The use of chloramine as a final disinfectant produces levels of cyanogen chloride that are 8-15 times higher than levels produced when chlorine is used (Jacangelo et al. 1989). Cyanogen chloride was qualitatively detected during a 1975 survey of Cincinnati drinking water (Kopfler et al. 1977). A 10-city survey that was conducted as part of the 1974 EPA National Organics Reconnaissance Survey revealed that cyanogen chloride was present in 8 of 10 drinking water supplies analyzed (no quantitative concentration values given) (Bedding et al. 1982). In a 1987 survey of 35 water utilities, the quarterly median cyanogen chloride concentrations in drinking water ranged from 0.45 to 0.80 pg/L. (Krasner et al. 1989). 82 5. POTENTIAL FOR HUMAN EXPOSURE 5.4.3 Soll Monitoring data regarding the cyanide levels in soil are limited. Cyanide has been identified in 390 of the 1,300 NPL hazardous waste sites that have been proposed for inclusion on the NPL (HAZDAT 1992). According to the CLP Statistical Database as of July 12, 1989, cyanide is estimated to occur at 8.5% of the sites evaluated at a geometric mean concentration of 1,236.8 mg/kg (CLPSD 1989). Note that the information used from the CLP Statistical Database includes data from NPL sites only. 5.4.4 Other Environmental Media The primary cyanide source in food is cyanogenic glycosides. Plants containing these natural compounds can produce hydrogen cyanide by acid hydrolysis or by the action of the enzyme glucosidases (EPA 1980; Fiksel et al. 1981). As many as 1,000 plants, including edible items such as almonds, pits from stone fruits (i.e., apricots, peaches, plums, cherries), sorghum, cassava, soybeans, spinach, lima beans, sweet potatoes, maize, millet, sugarcane, and bamboo shoots can produce hydrogen cyanide (Fiksel et al. 1981). Cyanide levels monitored in some of these foods are as follows: cereal grains and their products, 0.001-0.45 pg/g; soy protein products, 0.07-0.3 pg/g; cassava, 1 mg/g; and lima beans, 0.1-3 mg/g (Honig et al. 1983; Towill et al. 1978). The cyanide content in gari flour from a city market in Nigeria ranged from 10.6 to 22.1 mg/kg (Ukhun and Dibie 1989). In apricot pits, the cyanide concentration may vary from 89 to 2,170 mg/kg (wet weight) (Lasch and El Shawa 1981). The analysis of 233 samples of commercially available and homemade stone-fruit juices showed that pitted fruit juices contained less cyanides than nonpitted or partially pitted fruit juices (Stadelmann 1976). This indicates that the pits are the primary sources of cyanides in these juices. For example, the hydrogen cyanide content of a home-made mixed cherry juice from pitted fruits was 5.3 mg/L, compared to 23.5 mg/L in a cherry juice containing 100% crushed pits. This study also reported the following levels (median concentrations in mg/L) of hydrogen cyanide in commercial fruit juices: cherry, 4.6; apricot, 2.2; prune, 1.9; and peach, 2.9. Stadelmann (1976) recommended that the hydrogen cyanide content allowed in fruit juices should be set at a level of 5 mg/L. Cyanide can also be present in foodstuffs as residues from cyanide fumigation (Fiksel et al. 1981). Human exposure to naturally occurring cyanide in foods in the United States is expected to be low (Fiksel et al. 1981). Laetrile, a drug formerly used in the treatment of cancer (Khandekar and Edelman 1979), sodium nitroprusside, a drug used to reduce high blood pressure (Aitken et al. 1977), and a series of commercially important, simple, aliphatic nitrites (Willhite and Smith 1981) release cyanide upon metabolism. These drugs have been associated with human exposure to cyanide. Cyanide levels in mainstream (inhaled) smoke from U.S. commercial cigarettes vary from 10 to 400 pg per cigarette; levels in sidestream smoke vary between 0.6% and 27% of those in mainstream smoke (Fiksel et al. 1981). Cyanides have been detected in automobile exhaust. The average emission rate was 11-14 mg/mile for cars not equipped with catalytic converters and 1 mg/mile for cars with catalytic converters operating under optimum conditions. Cars with malfunctioning catalytic converters may emit as much or more hydrogen cyanide as cars without such equipment (Fiksel et al. 1981). 5.5 GENERAL POPULATION AND OCCUPATIONAL EXPOSURE The general population may be exposed to cyanide from inhaling air and ingesting food and drinking water contaminated with it. Since most of the cyanide in the air will be present as hydrogen cyanide (see 83 5. POTENTIAL FOR HUMAN EXPOSURE Section 5.3.2.1), the primary inhalation exposure to cyanide will occur from hydrogen cyanide. The concentration of hydrogen cyanide in the air of nonurban areas is =160-166 ppt (see Section 5.4.1). Based on an atmospheric hydrogen cyanide concentration of 170 ppt (190.9 ng/m®) and an average daily inhalation rate of 20 m?, the inhalation exposure to hydrogen cyanide is estimated to be 3.8 pg/day. In drinking water, cyanide will be present as cyanogen chloride (see Section 5.4.2). The mean cyanogen chloride concentration in drinking water ranges from 0.45 to 0.8 pg/L (see Section 5.4.2). Based on a daily drinking water consumption of 2 L, the daily intake of cyanogen chloride is estimated to be 0.9-1.6 pg, which is equivalent to 0.4-0.7 pg of hydrogen cyanide on the basis of molar ratio. The concentration value for cyanides in the total diet of a U.S. adult was not located in the available literature. Therefore, no estimate of daily cyanide intake from food can be made. Human exposure to cyanide from foods in which it occurs naturally in the United States is expected to be low, but is likely to exceed cyanide intake from inhalation of air and ingestion of drinking water (Fiksel et al. 1981). The allowable daily intake of cyanide is estimated to be 0.6 mg (Poitrast et al. 1988). The dietary cyanide intake of Tukanoan Indians in northwest Amazonia who rely heavily on high (>70% of all foods) cyanide-containing varieties of cassava was estimated to be >20 mg/day. The author did not find physical disorders in Tukanaon Indians attributable to high cassava diets, in contrast to observations about cassava-consuming populations in Africa (Dufour 1988). The variety of cassava may differ from area to area, and this appears to account for the lack of toxicity in some tribes and the high incidences in other tribes (Rosling 1988). The NOES conducted by NIOSH estimated that the statistics for workers potentially exposed to cyanide compounds in the United States are as follows (NIOSH 1989a): hydrogen cyanide, 3,780; sodium cyanide, 63,584; and potassium cyanide, 59,225. These numbers do not include workers potentially exposed to trade-name compounds that contain cyanides. Workers in various occupations may be exposed to cyanides. People possibly exposed to cyanide include workers involved in electroplating, metallurgy, pesticide application, firefighting, steel manufacturing, and gas works operations; workers involved in the manufacture of cyanides, adiponitrile and other simple, aliphatic nitriles, methyl methacrylate, cyanuric acid, dyes, pharmaceuticals, or chelating agents; and people who work in tanneries, blacksmithing, metal cleaning, photoengraving, or photography industries (Fiksel et al. 1981; Willhite and Smith 1981). Workers in the oil shale retorting industry may be exposed to cyanide because the offgas from the retorting process contains hydrogen cyanide (see Section 5.2.1). Medical and emergency personnel (e.g., police and firemen) who may be involved in resuscitation efforts or removal of gastric contents of postmortem victims of cyanide poisoning are potentially exposed to higher levels of cyanide (Andrews et al. 1989). In a survey of the plating facility of a national airline conducted by NIOSH in December 1981, the concentrations of hydrogen cyanide in three work areas ranged from 0.001 to 0.004 mg/m* (NIOSH 1982). The cyanide concentration in a work area beside a stripping tank of a plating facility of an electrical and electronic company in Waynesboro, Virginia, was 4.3 mg/m? (NIOSH 1976). Similarly, the concentration of cyanide in the breathing zone air of workers in a plating facility in Galion, Ohio, was 1.7 mg/m® (NIOSH 1978). Occupational exposures are expected to occur primarily through inhalation and, less frequently, through skin absorption. 5.6 POPULATIONS WITH POTENTIALLY HIGH EXPOSURES Workers involved in electroplating, metallurgy, pesticide application, firefighting, gas works operations, tanning, blacksmithing, metal cleaning, photoengraving, photography, and in the manufacture of steel, cyanides, adiponitrile and other nitriles, methyl methacrylate, cyanuric acid, dyes, pharmaceuticals, or chelating agents have the potential to be occupationally exposed to higher concentrations of cyanide than the general population. Among the general population, cigarette smokers and nonsmokers who inhale secondary smoke, residents who live near industrial sites releasing cyanides in the environment, residents who live near cyanide-containing hazardous waste sites, and people who consume foods high in glycogenic glycosides have the potential for exposure to cyanide at higher 84 5. POTENTIAL FOR HUMAN EXPOSURE concentrations. Data regarding the amount of cyanide exposure in any of these population groups were not located in the available literature. Two additional groups of people who may be at greater risk for cyanide exposure are those who are exposed to cyanide but are unable to smell the chemical (EPA 1987a) and patients with motor neuron disease (see Section 2.7). 5.7 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of cyanide is available. Where adequate information is not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of cyanide. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce or eliminate the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 5.7.1 Identification of Data Needs Physical and Chemical Properties. As reported in Section 3.2, the relevant physical and chemical properties of cyanide compounds are known. Certain physical parameters such as octanol/water partition coefficient and soil partition coefficient that are used generally for covalently bound organic compounds to predict environmental fate and transport are neither available nor useful for most of the ionic cyanide compounds. Production, Import/Export, Use, and Release and Disposal. Knowledge of a chemical’s production volume is important because it may indicate the magnitude of environmental contamination and human exposure. Data regarding the production, trend, use pattern, and disposal of commercially significant cyanide compounds are available (CMR 1990; SRI 1990). Although it is known that the import and export of hydrogen cyanide is insignificant compared to its production, recent import and export data for other cyanide compounds are difficult to obtain (USDA 1985). There are some less recent data regarding the release of cyanide in air, but more recent quantitative data regarding the release of cyanide compounds in air (Fiksel et al. 1981), water, and particularly soil are unavailable. According to the Emergency Planning and Community Right-to-Know Act of 1986, 42 U.S.C. Section 11023, industries are required to submit chemical release and off-site transfer information to the EPA. The Toxics Release Inventory (TRI), which contains this information for 1987, became available in May of 1989. This database will be updated yearly and should provide a list of industrial production facilities and emissions. Cyanide is naturally present in many foods high in cyanogenic glycosides (Fiksel et al. 1981; Honig et al. 1983; Towill et al. 1978). No information was located in the available literature to indicate that cyanide enters foods during processing or that cyanide is present in any consumer products. The two most likely sources of general population exposure to cyanide include people who inhale cigarette smoke (Fiksel et al. 1981) or individuals who are exposed to a house or other type of building fire (Andrews et al. 1989). There are EPA regulations regarding the disposal of cyanide wastes and OSHA regulations regarding the levels of hydrogen cyanide in workplaces. 85 5. POTENTIAL FOR HUMAN EXPOSURE Environmental Fate. The environmental fate of hydrogen cyanide gas in air is well studied (Cicerone and Zellner 1983; Fritz et al. 1982); however, it would be useful if the role of particulate cyanides (e.g., sodium cyanide, potassium cyanide) in determining the fate of total cyanides in the air was known. Given that hydrogen cyanide occurs in the atmosphere from both natural and anthropogenic processes (Cicerone and Zellner 1983; Fiksel et al. 1981), it would be useful if an estimate was available for the contribution of anthropogenic processes to the overall hydrogen cyanide burden in the atmosphere. It is generally known that volatilization and biodegradation will be important processes for the loss of cyanides in water (Callahan et al. 1979; Ludzack et al. 1951; Raef et al. 1977; Towill et al. 1978), but no experimental or estimated values for the half-life of cyanides in ambient water are available. No comprehensive data regarding the role of sorption in determining the fate of cyanides in water are available. It is generally known that volatilization from soil surfaces and biodegradation play significant roles in the loss of cyanides in soil (Towill et al. 1978), but no quantitative data regarding the half-life of cyanides in ambient soil are available. The elucidation of the role of cyanide complexation by metals in soil and sediment in controlling the fate of cyanide would be useful. Bioavailability from Environmental Media. The environmental factors that may influence the bioavailability of cyanide from contaminated air, water, soil, or plant material have not been studied. Since the cyanides are not strongly sorbed to soil and sediments (Callahan et al. 1979), the role of sorption may not be significant in determining the bioavailability of cyanides from different soils or waters. The bioavailability of cyanide from an environmental medium is expected to increase if the cyanide is present in water-soluble forms, such as ions or soluble complexes. The pH of a medium may also be significant in determining the bioavailability because hydrogen cyanide gas may be released as the pH of the medium decreases (Callahan et al. 1979; Towill et al. 1978). Data delineating the factors changing the bioavailability of cyanide compounds from environmental media need further development, since the absorption studies discussed in Section 2.3.1 have been performed with the pure chemical. Food Chain Bioaccumulation. Simple cyanide compounds do not bioconcentrate in fish (Callahan et al. 1979; EPA 1985a). It would be useful to determine the bioconcentration potential for cyanide in fish from water dosed with less toxic and water-soluble cyanide complexes. There is no indication of biomagnification of cyanides in aquatic and terrestrial food chains. Because of the high toxicity of cyanides at high doses and rapid metabolism at low doses, biomagnification of cyanide in animals seems unlikely. More experimental data regarding the biomagnification potential of complex cyanides, however, would be desirable. Exposure Levels in Environmental Media. Data regarding the cyanide levels in ambient air and drinking water are lacking; therefore, it is not possible to estimate exposure levels to cyanides from inhaling ambient air and ingesting drinking water. Although the cyanide contents in certain foods are known (Fiksel et al. 1981; Honig et al. 1983; Towill et al. 1978), the cyanide content of a total diet sample consumed by an average adult is not known; therefore, the dietary exposure of an average person to cyanide remains unknown. Reliable monitoring data for the levels of cyanide in air, water, and total diet samples would be useful in estimating exposure from each source. Additional data regarding the levels of cyanide in soils will also be useful. It will also be useful to develop data that would clearly establish whether cyanides pose acute or chronic exposure hazards for residents in the vicinity of hazardous waste sites. Exposure Levels in Humans. The levels of cyanide in various human tissues and body fluids of both control groups and occupationally exposed groups of the population are available (see Sections 2.3.4 and 2.5.1). However, data regarding the levels of cyanide in body tissues or fluids for population living near hazardous waste sites are not available. Such data would be useful in assessing whether this group of people are being exposed to cyanides at levels higher than background levels. 86 5. POTENTIAL FOR HUMAN EXPOSURE Exposure Registries. No exposure registries for cyanide were located. This compound is not currently one of the compounds for which a subregistry has been established in the National Exposure Registry. The compound will be considered in the future when chemical selection is made for subregistries to be established. The information that is amassed in the National Exposure Registry facilitates the epidemiological research needed to assess adverse health outcomes that may be related to the exposure to this compound. 5.7.2 On-going Studies A search of the Federal Research in Progress database indicates that no long-term research studies are in progress to fill in the data gaps discussed in Section 5.7.1. 87 6. ANALYTICAL METHODS The purpose of this chapter is to describe the analytical methods that are available for detecting and/or measuring and monitoring cyanide in environmental media and in biological samples. The intent is not to provide an exhaustive list of analytical methods that could be used to detect and quantify cyanide. Rather, the intention is to identify well-established methods that are used as the standard methods of analysis. Many of the analytical methods used to detect cyanide in environmental samples are the methods approved by federal organizations such as EPA and the National Institute for Occupational Safety and Health (NIOSH). Other methods presented in this chapter are those that are approved by groups such as the Association of Official Analytical Chemists (AOAC) and the American Public Health Association (APHA). Additionally, analytical methods are included that refine previously used methods to obtain lower detection limits, and/or to improve accuracy and precision. 6.1 BIOLOGICAL MATERIALS Some of the common methods available for determining cyanide in biological media are reported in Table 6-1. Since cyanide forms volatile hydrogen cyanide gas, tissue sampling techniques, storage, and cyanide analysis must be done with caution. The choice of tissues and the factors influencing measured cyanide concentrations are also important (Ballantyne 1983c). Moreover, the organ distribution of cyanide varies considerably with the administration route and the animal species (Way 1984). Cyanide in the body is biotransformed to thiocyanate quickly. The relative proportion of cyanide to thiocyanate in body fluids is =1:1000 (Pettigrew and Fell 1973). Some authors have determined thiocyanate in body fluids as a measure of cyanide exposure, while others measure cyanide concentrations in body fluids as a measure of cyanide exposure. The determination of cyanide in body fluids requires the separation of cyanide from thiocyanate, usually by distillation of cyanides. Cyanide in blood is almost exclusively localized to the erythrocytes, whereas thiocyanate is confined to plasma (Lundquist and Sorbo 1989). Sodium thiosulfate, a common cyanide antagonist that acts as an interference, can be eliminated by using a buffered solution at pH 5.2 as the acidifying agent for cyanide microdiffusion (Sylvester et al. 1982; Way 1984). The microdiffusion technique, when employed with spectrophotofluorometric methods for quantification, provides one of the more sensitive methods for determining cyanides in body fluids (Way 1984). Some other methods available to detect cyanide in micro-amounts of biological samples or low concentrations of cyanide in biological samples are high performance liquid chromatography/fluorometric detection (Toida et al. 1984), gas chromatography/electron capture detection (Maseda et al. 1989), volumetric method (Westley and Westley 1989), and enzyme/spectrophotometric method (Fonong 1987). 6.2 ENVIRONMENTAL SAMPLES Because of the history of cyanide poisoning, numerous reports dealing with the identification and quantification of cyanide in air, water, and other environmental media are available. One of the most significant problems in cyanide monitoring is the instability of the collected samples (Cassinelli 1986). For example, hydrogen cyanide is usually collected in sodium hydroxide solution at pH 211 to avoid volatilization loss of molecular hydrogen cyanide. However, carbon dioxide from air may react with the solution during storage, thereby lowering the pH and releasing hydrogen cyanide gas. Oxidizing agents in solution may transform cyanide during storage and handling. Ferrocyanide and ferricyanide complexes of cyanide undergo photodecomposition with ultraviolet light. Particulate cyanides are known to decompose in moist air with the liberation of hydrogen cyanide. The recommended method for the storage of cyanide samples is to collect the samples at pH 12-12.5 in closed, dark bottles and store them in a cool, dark place. It is also recommended that the samples be analyzed immediately upon collection. The sample handling and preservation methods have been discussed (Cassinelli 1986; Egekeze and Ochme 1979, 1983a). Inorganic cyanides in water can be present both as complexed and free cyanide. Cyanide in water is usually determined in three different forms: free cyanide, cyanide amenable to chlorination, and total cyanide. Free cyanides such as sodium cyanide, potassium cyanide, and hydrogen cyanide are readily TABLE 6-1. Analytical Methods for Determining Cyanide in Biological Materials Sample matrix Preparation method Analytical method Sample detection limit Percent recovery Reference Blood Blood Blood Plasma Acidified (pH 5.2) sample in a in a Conway microdiffusion cell is absorbed in NaOH. NaOH solution treated with chloramine T-phosphate and pyridine- pyrazolone reagent Acidified (buffered at pH 5.2) sample in a Conway microdif- fusion cell is absorbed in NaOH. NaOH solution buffered at pH 7.5 mixed with pyridoxal- HCI. Solution heated to 50°C or mixed with p-benzoquinone in dimethyl sulfoxide Centrifuge with NaNO,, vortex precipitate with HCIO4, mix supernate with NaOCl, barbituric acid and pyridine reagent Deproteinized by adding trichloroacetic acid. Super- natant brominated and treated with pyridine-p-phenylene diamine Spectrophotometric (total cyanide) Spectrophotofluorometric (total cyanide) Spectrophotometric Spectrophotometric (thiocyanate-cyanide determination) 0.1 ppm 0.025 ppm 0.03 ppm =0.07 ppm No data No data 93% at 1.3 ppm 96% at 0.14 ppm Morgan and Way 1980; Way 1984 Ganjeloo et al. 1980; Morgan and Way 1980; Way 1984 Lundquist and Sorbo 1989 Pettigrew and Fell 1972 SAOHL3N TVOILATYNY 9 88 TABLE 6-1 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Erythrocyte Nitrogen passed through Spectrophotometric No data 93-97% McMillan and suspension sample buffered at pH 5, and (thiocyanate-cyanide Svoboda 1982 hydrogen cyanide absorbed in determination) sodium hydroxide; thiocyanate converted to cyanide by potassium for permanganate oxidation Blood and liver Homogenized sample acid Specific ion electrode No data 100-109% at ~~ Egekeze and Oehme digested at 90°C. Released (total cyanide) 0.3-130 ppb 1979 HCN swept by air is passed through a lead acetate and a NaOH absorption tube Blood and urine Acidified sample (pH 5.2) in a Spectrophotofluorometric 0.0008 ppm 66-82.6% at Sano et al. 1989 Conway microdiffusion cell is 0.0013-0.13 absorbed in NaOH. NaOH ppm (blood); solution treated with 75.6-82% at naphthalene-2,3-dialdehyde and 0.0013-0.13 taurine ppm (urine) Urine Diluted sample brominated Spectrophotometric =0.07 ppm 88% at Pettigrew and Fell with Br, and treated with (thiocyanate-cyanide 0.6 ppm 1972 pyridine p-phenylenediamine determination) SAOHL3N TVOLLATVYNY 9 68 TABLE 6-1 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Biological Acidified (buffered at pH 5.2) Specific ion electrode 0.03 ppm No data Way 1984 fluids sample in a Conway micro- (total cyanide) diffusion cell is absorbed in NaOH. Br, = bromine; HCI = hydrogen chloride; HClO, = perchloric acid; HCN = hydrogen cyanide; NaNO, = sodium nitrite; NaOCl = sodium hypochlorite; NaOH = sodium hydroxide SAOHL3NW TVOILATVYNY 9 06 91 6. ANALYTICAL METHODS ionized to the cyanide ion under the conditions used in most common analytical techniques. Methods for determining cyanide amenable to chlorination measure simple metal cyanides and most complex cyanides with the exception of iron cyanides. Total cyanide is a measure of all cyanides including iron cyanide complexes. Table 6-2 lists the analytical methods for determining cyanides that may be present in three different forms. Cyanide determination in air, as reported in Table 6-2, is usually performed by distinguishing between two forms of cyanides (i.e., hydrogen cyanide gas and particulate cyanides). Mixed cellulose ester membrane filters are usually used to collect particulate cyanides, and the hydrogen cyanide gas that passes through the membrane is trapped in sodium hydroxide for hydrogen cyanide determination. The collected particulate cyanides can be quantified separately after acid distillation. Many particle cyanides, however, decompose in moist air with the liberation of hydrogen cyanide, thereby giving erroneously high values for hydrogen cyanide by this method. The decomposition of particle cyanide is dependent on the relative humidity of air, the particle size, and the total surface area of the collected particles (Cassinelli 1986). Almost all the available methods for determining cyanide in water can be applied to the analysis of cyanides in air because most quantification methods for air samples ultimately involve the determination of the cyanide ion in solution. The three commonly used methods, colorimetric, titrimetric, and electrochemical, may all suffer from interference problems unless proper precautions are taken. Methods using specific ion electrodes (electrochemical) respond to numerous interferences (sulfur, chlorine, iodine, bromine, cadmium, silver, zinc, copper, nickel, and mercury) (Cassinelli 1986). Sulfide, certain oxidizing agents, nitrate or nitrite, thiocyanate, aldehydes, and ketones may interfere under acid distillation conditions, thus producing erroneous results from both colorimetric and titrimetric methods. In addition, fatty acids in samples may distill over and form soaps under alkaline titration conditions, thus causing interference in the titrimetric method (EPA 1983a). Of the commonly used methods, the colorimetric method and the electrochemical (specific ion electrode) method have satisfactory sensitivity for cyanide determination in polluted samples, and a method employing infrared absorption instrumentation aboard an aircraft has been used to determine the concentration of hydrogen cyanide in the troposphere (Cicerone and Zellner 1983). Suitable methods are also not available for the determination of the concentrations of cyanides present in soils at low levels. The more recently developed ion-chromatographic/amperometric determination may have higher sensitivity. However, neither of these methods described in Table 6-2 have adequate sensitivity to determine the level of cyanide in ambient air and most surface waters where the cyanide concentration is <3.5 ppb. A collaborative study conducted by Britton et al. (1984) to determine the most reliable method among the three most commonly used methods (two colorimetric methods and the electrode method) showed that both pyridine- barbituric acid and pyridine-pyrazolone have similar statistical accuracy. The pyridine-barbituric acid method was preferred by Britton et al. (1984) over the pyridine-pyrazolone method for its convenience (quicker analysis time) rather than the statistical accuracy of data. The electrode method had higher data variability. Several less commonly used methods are available for cyanide quantification. One of these methods uses chloramine-T to oxidize cyanide to cyanogen chloride for subsequent extraction with hexane for quantification by electron capture detection (detection limit of 0.25 ppm) (Way 1984). In another method, cyanide is measured indirectly after the precipitation of silver cyanide with excess silver nitrate and then the excess silver in the supernatant is determined by atomic absorption spectrometry (Way 1984). Continuous monitoring instruments based on diffusion and amperometric (Fogg and Alonso 1987) or spectrophotometric (Meeussen et al. 1989; Zhu and Fang 1987) methods for the quantification of diffused hydrogen cyanide are also available. Other methods include gas chromatographic-flame ionization detection of cyanogen chloride and cyanogen (Brown et al. 1986), jon chromatography with conductivity detection (Nonomura 1987) of cyanide, and spectrophotometric determination following ultraviolet-induced photodecomposition to detect soluble hexacyanoferrate complexes in water (Ohno 1989). The chromatographic-flame ionization detection method is one of the most sensitive methods for the determination of cyanogen and cyanogen chloride. TABLE 6-2. Analytical Methods for Determining Cyanide in Environmental Samples Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Occupational Filtered air passed through midget Specific ion electrode 2.5 pg CN- 96.7% at NIOSH 1989a air impinger containing NaOH. Extract (HCN cyanide salts) 5-21 mg/m3 filter with NaOH. Sulfide inter- ference removed by addition of H,0,. Determine cyanide both in filter extract and impinger solution Air Cellulose-ester-membrane-filtered Ion-chromatography/ 0.04 ppm (for 91% at air Cassinelli 1986 air passed through midget impinger amperometric detection 2.6 L of air) flow rate of containing Cd(NO3),/Na,CO3/ (HCN only) 0.171 L/minute NaH,BOs/ethylenediamine Air Cellulose-ester-membrane-filtered Ion-chromatography/ No data 100-109 at Dolzine et al. air passed through midget impinger amperometric detector 5-20 ppm 1982 containing NaOH. Solution heated at 110°C to convert NaCN to sodium formate Water (drinking, Sample acidified and reflux- Spectrophotometric (EPA 0.02 ppm 85-102% at EPA 1983a surface, saline, distilled; released HCN absorbed Method 335.2) 0.28-0.62 domestic, and in NaOH scrubber. Absorbing (total cyanide) ppm industrial waste) solution treated with chloramine-T and pyridine-pyrazolone or pyridine barbituric acid SAOHL3N TVOILATYNY 9 26 TABLE 6-2 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Water (drinking, Sample chlorinated at pH 11-12 Spectrophotometric (EPA No data No data EPA 1983a surface, saline, and CICN driven off. Residual Method 335.1) (cyanide domestic, and sample acidified and reflux- amenable to chlorination) industrial waste) distilled; released HCN absorbed in NaOH. Absorbing solution treated with chloramine-T and pyridine-pyrazolone or pyridine- barbituric acid Water (drinking, Sample acidified and reflux- Titrimetric (EPA Method 1 ppm No data EPA 1983a surface, saline, distilled; released HCN absorbed 335.2) (total cyanide) domestic, and in NaOH. Absorbing solution industrial waste) titrated with AgNO; in presence of p-dimethylaminobenzal- rhodanine indicator Water None Ion-chromatography/ 2 ppb 100-112% Rocklin and amperometric detector Johnson 1983 (free and a few complexed cyanides) Water Acidified (pH 5.0) sample in a Potentiometric 0.018 ppm 96.5-103.9% Rubio et al. microdiffusion cell is absorbed in NaOH 0.037-3.49 mg/L 1987 SAOHL3W TVOLLATYNY 9 €6 TABLE 6-2 (Continued) Sample detection Percent Sample matrix Preparation method Analytical method limit recovery Reference Waste or Sample acidified and reflux- Titrimetric or colorimetric 0.1 ppm (Titrimetric) EPA 1988 leachate distilled; released HCN (EPA CLP Method 9010) (titrimetric) 85-102% at absorbed in NaOH. Absorbing (total cyanide) 0.02 ppm 0.06-0.62 solution titrated with AgNO3 (colorimetric) mg/L CN in presence of p-dimethylamino- benzal-rhodanine indicator or cyanide determined colorimetry with pyridine-barbituric acid Solid waste or Extract sample with water at Titrimetric or colorimetric No data 60-90% (solid) EPA 1988 oil waste pH 210 (EPA CLP Method 9010) 88-92% (oil) (total cyanide) Food (cereal Extract with water/acetonitrile; GC/ECD at low detection =0.1 ppm 90% Heuser and and other dry extract voltage (free cyanide) Scudmore 1969 foodstuffs) Food (soybean Sample mixed with water, lead Spectrophotometric No data 32-80% Honig et al. and soybean nitrate, tartaric acid, and anti- (total cyanide) 1983 products) foaming agent. Mixture acidified Distillate complexed with pyridine- barbituric acid AgNO; = silver nitrate; Cd(NO3), = cadmium nitrate; CICN = cyanogen chloride; CLP = Contract Laboratory Program; CN” = cyanide ion; EPA = Environmental Protection Agency; GC/ECD = gas chromatograph/electron capture detector; HCN = hydrogen cyanide; H,0, = hydrogen peroxide; HySO,4 = sulfuric acid; NayCO5 = sodium carbonate; NaH,BO3 = sodium dihydrogen borate; NaOH = sodium hydroxide SAOHL3N TVOILATYNY 9 v6 95 6. ANALYTICAL METHODS 6.3 ADEQUACY OF THE DATABASE Section 104(i)(5) of CERCLA directs the Administrator of ATSDR (in consultation with the Administrator of EPA and agencies and programs of the Public Health Service) to assess whether adequate information on the health effects of cyanide is available. Where adequate information is not available, ATSDR, in conjunction with NTP, is required to assure the initiation of a program of research designed to determine the health effects (and techniques for developing methods to determine such health effects) of cyanide. The following categories of possible data needs have been identified by a joint team of scientists from ATSDR, NTP, and EPA. They are defined as substance-specific informational needs that if met would reduce or eliminate the uncertainties of human health assessment. This definition should not be interpreted to mean that all data needs discussed in this section must be filled. In the future, the identified data needs will be evaluated and prioritized, and a substance-specific research agenda will be proposed. 6.3.1 Identification of Data Needs Methods for Determining Biomarkers of Exposure and Effect. Besides environmental exposure, exposure to cyanide can also occur from consumption of cyanide-containing food, metabolism of certain drugs, and smoking cigarettes (see Section 2.5.1). Since so many factors can influence cyanide exposure, the exact correlation between cyanide concentrations in the body and its level in the environment has not been made. Therefore, measuring cyanide and/or thiocyanate levels in blood and urine cannot be used as a biomarker for exposure to low cyanide concentrations. Analytical methods of required sensitivity and reliability to detect cyanide and thiocyanate in blood, plasma, and urine of both unexposed and exposed persons are available (see Table 6-1). Further studies determining biomarkers for exposure to low cyanide concentrations would be useful. Although certain effects, such as cyanosis and endemic goiter, have been associated with cyanide exposure (see Section 2.5.2), a positive correlation between cyanide exposure and one of its effects has not yet been established. Additional studies establishing a correlation between cyanide exposure and one of its effects will be useful in diagnosing cyanide exposure. Methods for Determining Parent Compounds and Degradation Products in Environmental Media. The concentration of hydrogen cyanide in most ambient air is so low that it is beyond the detection limit of the standard analytical methods. An infrared absorption method of a large vertical tropospheric column was used to measure the hydrogen cyanide concentration in the troposphere (Cicerone and Zellner 1983). Similarly, ground- based millimeter wave emission spectroscopy was used to measure stratospheric concentration of hydrogen cyanide (Jaramillo et al. 1989). Since suitable standard analytical methods are unavailable, the hydrogen cyanide level in ambient air generally remains unreported. Similarly, the level of cyanogen chloride in drinking water ranges from 0.45 to 0.80 ppb (Krasner et al. 1989), which is beyond the detection limit of the standard analytical methods without concentration and trapping procedures. Cyanogen chloride in water was determined by a purge and trap gas chromatography-mass spectrometric method (Krasner et al. 1989), a method that is not available to many laboratories. There is, therefore, a need to develop standard analytical methods capable of quantitating hydrogen cyanide in air and cyanogen chloride in water at levels that are generally found in these media. Cyanide metabolizes in the human body to thiocyanate, and its biodegradation products include ammonia, carbon dioxide, nitrate, or nitrogen (Richards and Shieh 1989). The detection of thiocyanate in body fluid may be indicative of cyanide exposure. Similarly, the amounts of cyanide degradation products formed in an environmental medium could be used to measure its biodegradation rate. Suitable analytical methods are available to detect all of these compounds (Pettigrew and Fell 1973; Richards and Shieh 1989). 96 6. ANALYTICAL METHODS 6.3.2 On-going Studies No on-going studies regarding the determination of low levels of hydrogen cyanide in air and cyanogen chloride in water or the identification of a biological effect that correlates with exposure to cyanide were located in the available literature. 97 7. REGULATIONS AND ADVISORIES The national and state regulations and guidelines regarding human exposure to cyanide are summarized in Table 7-1. Cyanide is regulated by the Clean Water Act Effluent Guidelines for the following industrial point sources: electroplating, manufacturing of iron, steel, and batteries, heat product processing, nonferrous metal forming, aluminum forming, photography, and industries that use, process, or manufacture organic and inorganic chemicals, steam electric, ferroalloys, and pharmaceuticals (EPA 1988a). There is a zero discharge limitation for the following industries: asbestos, timber products processing, mineral mining, gum and wood and carbon black manufacturing. Tolerances for hydrogen cyanide in foods when used as a post-harvest fumigant range from 25 ppm in dried beans, peas, and nuts to 250 ppm in spices (EPA 1988c). Post-harvest residue of hydrogen cyanide in grains is 75 ppm (EPA 1988c) and is 25 ppm of calcium cyanide calculated as hydrogen cyanide (EPA 1988b). Federal law (Section 302 of SARA) requires any facility with extremely hazardous substance present in excess of the threshold planning quantity (TPQ) to notify the state emergency planning commission. TPQs for cyanide compounds are 100 pounds for hydrocyanic acid, potassium cyanide, and sodium cyanide, and 500 pounds for potassium silver cyanide (EPA 1987). Oral references doses (RfDs) for free cyanide, hydrogen cyanide, sodium cyanide, potassium cyanide, calcium cyanide, barium cyanide, cyanogen, chlorine cyanide, copper cyanide, zinc cyanide, silver cyanide, and potassium silver cyanide have been verified and are available on IRIS (1990) (see Table 7-1). The RfDs for barium and copper cyanide are not based on the toxicity of cyanide. All remaining RfDs are based on the NOAEL of 10.4 mg/kg/day for systemic effects in rats fed hydrogen cyanide for 2 years (Howard and Hanzal 1955). There are no data indicating that cyanides are carcinogenic. Cyanide has been assigned to EPA classification D-- not classifiable as to human carcinogenicity (EPA 1990a). 7. REGULATIONS AND ADVISORIES TABLE 7-1. Regulations and Guidelines Applicable to Cyanide Agency Description Information References NATIONAL Regulations: a. Air: OSHA TWA-PEL (cyanide salts) 5 mg/m OSHA 1989 (29 CFR 1910) STEL (hydrogen cyanide) 4.7 ppm OSHA 1989 (29 CFR 1910) b. Water: EPA ODW MCLG (proposed for cyanide) 200 pg/L EPA 1990b (40 CFR 141, 142, 143) c. Other: EPA RQ (ruled): EPA 1989c (54 FR) Hydrogen cyanide 10 Ib (4.54 kg) Barium cyanide 10 Ib (4.54 kg) Calcium cyanide 10 1b (4.54 kg) Copper cyanide 10 1b (4.54 kg) Cyanogen cyanide 10 1b (4.54 kg) Potassium cyanide 10 1b (4.54 kg) Sodium cyanide 10 1b (4.54 kg) Zinc cyanide 10 Ib (4.54 kg) Cyanogen 100 1b Potassium silver cyanide 11b Silver cyanide 11b Tolerated residue (hydrogen cyanide): Spices 250 ppm EPA 1988c (40 CFR 180.130) Citrus fruits 50 ppm EPA 1988c (40 CFR 180.130) Almonds, cocoa beans, nuts 25 ppm EPA 1988c (40 CFR 180.130) Grains 25-75 ppm EPA 1988a (40 CFR 180.125); EPA 1988¢c (40 CFR 180.130) Vegetables 5 ppm EPA 1988a (40 CFR 180.125) Guidelines: a. Air ACGIH Ceiling (hydrogen cyanide) 10 ppm (11 mg/m’) ACGIH 1991 TWA (cyanide) S mg/m NIOSH 10-minute ceiling (cyanides) 5 mg/m’ NIOSH 1990 99 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References National (Continued) b. Water: EPA-OWRS Ambient water quality criterion 200 pg/L IRIS 1992 for cyanide EPA-ODW DWEL (child) 22x10! mg/L IRIS 1992 DWEL (adult) 7.7x10°1 mg/L IRIS 1992 c. Other: EPA RfD (chronic oral): IRIS 1992 Cyanide (free) 2x10 mg/kg/day Hydrogen cyanide 2x10°2 mg/kg/day Calcium cyanide 4x102 mg/kg/day Chlorine cyanide 5x10"2 mg/kg/day Cyanogen 4x1072 mg/kg/day Potassium cyanide 5x1072 mg/kg/day Potassium silver cyanide 2x10"! mg/kg/day Silver cyanide 1x10° mg/kg/day Sodium cyanide 4x102 mg/kg/day Zinc cyanide 5x10°2 mg/kg/day EPA Cancer classification Dp? STATE Regulations and Guidelines: a. Air: Acceptable ambient air concentrations: Hydrogen cyanide: Arizona 40 pg/m> (24 hr) NATICH 1992 Connecticut 220 pg/m> (8 hr) NATICH 1992 Kentucky 1.792x10°3 1b (1 hr) State of Kentucky 1988 North Carolina 1 mg/m (1 hr) NATICH 1992 0.12 mg/m (24 hr) NATICH 1992 North Dakota 0.1 mg/m? (1 hr) NATICH 1992 Nevada 0.238 mn (8 hr) NATICH 1992 New York 33 pg/m> (1 hr) NATICH 1992 Oklahoma 51 pg/m> (24 hr) NATICH 1992 South Carolina 250 pg/m> (24 hr) NATICH 1992 Texas 50 pg/m> (30 min) NATICH 1992 Virginia 80 pg/m3 (24 hr) NATICH 1992 Cyanogen: Connecticut 400 pg/m> (8 hr) NATICH 1992 Florida - Tampa 0.2 mg/m> (8 hr) NATICH 1992 Kentucky 5.103x1073 1b (1 hr) State of Kentucky 1988 Nevada 0.476 mg/m> (8 hr) NATICH 1992 New York 66.7 pg/m (1yn NATICH 1992 North Dakota 0.2 mg/m> (24 hr) NATICH 1992 South Carolina 500 pg/m3 (24 hn) NATICH 1992 Texas 210 pg/m3 (30 min) NATICH 1992 Virginia 350 pg/m> (24 hr) NATICH 1992 100 7. REGULATIONS AND ADVISORIES TABLE 7-1 (Continued) Agency Description Information References STATE (Continued) Potassium cyanide: Nevada 0.119 mg/m? (8 hr) NATICH 1992 New York 17 pg/m> (1 hr) NATICH 1992 Texas 50 pg/m> (30 min) NATICH 1992 Sodium cyanide: Connecticut 100 pg/m> (8 hr) NATICH 1992 North Dakota 50 pg/m> (8 hr) NATICH 1992 South Dakota 100 pg/m> (8 hr) NATICH 1992 Texas 50 pg/m> (30 min) NATICH 1992 Vermont 500 pg/m> (8 hr) NATICH 1992 Virginia 83 pg/m> (24 hr) NATICH 1992 b. Water: Acceptable ambient water concentrations FSTRAC 1990 for cyanide Arizona 220 pg/L Kansas 154 pg/L Massachusetts 140 pg/L Maine 154 pg/L Minnesota 154 pg/L New Hampshire 154 pg/L Rhode Island 150 pg/L Vermont 154 pg/L 3Group D: Not classifiable as a human carcinogen. ACGIH = American Conference of Governmental Industrial Hygienists; DWEL = Drinking water equivalent level/lifetime health advisory; EPA = Environmental Protection Agency; MCLG = Maximum contaminant level goal; ODW = Office of Drinking Water; OWRS = Office of Water Regulations and Standards; OSHA = Occupational Safety and Health Administration; PEL = Permissible exposure level; RfD = Reference dose; RQ = Reportable quantity; STEL = Short-term exposure limit; TWA = Time-weighted average 101 8. REFERENCES *ACGIH. 1986. Documentation of the threshold limit values and biological exposure indices. 5th ed. Cincinnati, OH: American Conference of Governmental Industrial Hygienists, 154, 155, 314. *ACGIH. 1991. Threshold limit values for chemical substances and physical agents and biological exposure indices for 1991-1992. American Conference of Governmental Industrial Hygienists. Cincinnati, OH. *Adams DJ, Takeda K, Umbach JA. 1985. Inhibitors of calcium buffering depress evoked transmitter release at the squid giant synapse. J Physiol 369:145-159. *Ahmed AE, Farooqui MYH. 1982. Comparative toxicities of aliphatic nitriles. Toxicol Lett 12:157-163. *Aitken D, West D, Smith F, et al. 1977. Cyanide toxicity following nitroprusside-induced hypotension. Can Anaesth Soc J 24:651-660. *Alexander K, Baskin SI. 1987. Mechanistic studies of guinea-pig liver rhodanese [Abstract]. Fed Proc 46:954. *Allen DG, Smith GL. 1985. Intracellular calcium in metabolically depleted ferret ventricular muscle during exposure to cyanide and its removal. J Physiol 269:1-92. *Amoore JE, Hautala E. 1983. Odor as an aid to chemical safety: Odor thresholds compared with threshold limit values and volatilities for 214 industrial chemicals in air and water dilution. J Appl Toxicol 3:272-290. *Andrews JM, Sweeney ES, Grey TC, et al. 1989. The biohazard potential of cyanide poisoning during postmortem examination. J Forensic Sci 34:1280-1284. *Anon. 1990. Health assessment for ALSCO anaconda national priorities list. NTIS PB90-100330. *Ansell M, Lewis FAS. 1970. A review of cyanide concentrations found in human organs: A survey of literature concerning cyanide metabolism, ‘normal,’ non-fatal, and fatal body cyanide levels. J Forensic Med 17:148-155. *Ardelt BK, Borowitz JL, Isom GE. 1989. Brain lipid peroxidation and antioxidant protectant mechanisms following acute cyanide intoxication. Toxicology 56:147-154. *Ballantyne B. 1983a. The influence of exposure route and species on the acute lethal toxicity and tissue concentrations of cyanide. In: Hayes, AW, Schnell RC, Miya TS, eds. Developments in the science and practice of toxicology location of publisher. New York, NY: Elsevier Science Publishers B.V., 583-586. *Ballantyne B. 1983b. Acute systemic toxicity of cyanides by topical application to the eye. Journal of Toxicology, Cutaneous and Ocular Toxicology 2:119-129. *Ballantyne B. 1983c. Artifacts in the definition of toxicity by cyanides and cyanogens. Fundam Appl Toxicol 3:400-408. *Cited in text 102 8. REFERENCES *Ballantyne B. 1988. Toxicology and hazard evaluation of cyanide fumigation powders. Clin Toxicol 26:325- 33s. *Ballantyne G, Bright J, Swanston DW, et al. 1972. Toxicity and distribution of free cyanides given intramuscularly. Med Sci Law 12:209-219. *Barnes DG, Dourson M. 1988. Reference dose (RfD): Description and use in health risk assessment. Regul Toxicol Pharmacol 8:471-486. *Baskin S, Kirby S. 1990. Effect of sodium tetrathionate on cyanide conversion to thiocyanate by enzymatic and non-enzymatic mechanisms [Abstract]. The Toxicologist 10:326. *Bass NH. 1968. Pathogenesis of myelin lesions in experimental cyanide encephalopathy. Neurology 18:167-1717. *Basu TK. 1983. High-dose ascorbic acid decreases detoxification of cyanide derived from amygdalin (laetrile): Studies in guinea pigs. Can J Physiol Pharmacol 61:1426-1430. *Bedding ND, McIntyre AE, Perry R, et al. 1982. Organic contaminants in the aquatic environment. I. Sources and occurrence. Sci Total Environ 25:143-167. *Belly RT, Goodhue CT. 1976. A radiorespirometric technique for measuring the biodegradation of specific components in a complex effluent In: Sharpley JM, Kaplan AM, eds. Proceedings of the 3rd International Biodegradation Symposium, 1975. Barking, England: Applied Science, 1103-1107. *Benabid MAS, Decorps M, Remy C. 1987. *'P nuclear magnetic resonance in_vivo spectroscopy of the metabolic changes induced in the awake rat brain during KCN intoxication and its reversal by hydroxocobalamine. J Neurochem 48:804-808. *Berlin C. 1977. Cyanide poisoning--A challenge. Arch Intern Med 137:993-994. *Birky MM, Clarke FB. 1981. Inhalation of toxic products from fires. Bull NY Acad Med 57:997-1013. *Blanc P, Hogan M, Mallin K, et al. 1985. Cyanide intoxication among silver-reclaiming workers. J Am Med Assoc 253:367-371. *Bonsall JL. 1984. Survival without sequelae following exposure to 500 mg/m® of hydrogen cyanide. Hum Toxicol 3:57-60. *Borowitz JL, Born GS, Isom GE. 1988. Potentiation of evoked adrenal catecholamine release by cyanide: Possible role of calcium. Toxicology 50:37-45. Boxer GE, Rickards JC. 1952. Studies on the metabolism of the carbon of cyanide and thiocyanate. Arch Biochem Biophys 36:7-26. *Brandt-Rauf PW, Fallon LF Jr, Tarantini T, et al. 1988. Health hazards of fire fighters exposure assessment. Br J Ind Med 45:606-612. 103 8. REFERENCES *Brierley JB, Brown AW, Calverley J. 1976. Cyanide intoxication in the rat: Physiological and neuropathological aspects. J Neurol Neurosurg Psychiatry 39:129-140. *Bright JE, Marrs TC. 1987. Effect of p-aminopropiophenone (PAPP), a cyanide antidote, on cyanide given by intravenous infusion. Hum Toxicol 6:133-137. Bright JE, Marrs TC. 1988. Pharmacokinetics of intravenous potassium cyanide. Hum Toxicol 7:183-186. *Brown PN, Jayson GG, Wilkinson MC. 1986. Determination of cyanogen and cyanogen chloride using gas chromatography with a flame ionization detector. Chromatographia 21:161-164. *Buzaleh AM, Vazquez EB, Batlle AMC. 1989. Cyanide intoxication--I. An oral chronic animal model. Gen Pharmacol 20:323-327. *Callahan MA, Slimak MW, Gabel NW, et al. 1979. Water-related environmental fate of 129 priority pollutants. Vol. 1. EPA, Office of Water Planning and Standards, Office of Water and Waste Management, Washington, DC. *Carella F, Grassi MP, Savoiardo M, et al. 1988. Dystonic-parkinsonian syndrome after cyanide poisoning: Clinical and MRI findings. J Neurol Neurosurg Psychiatry 51:1345-1348. *Carotti AA, Kaiser ER. 1972. Concentrations of twenty gaseous chemical species in the flue gas of a municipal incinerator. J Air Pollut Control Assoc 22:224-253. *Cassinelli ME. 1986. Progress toward developing a monitoring method for hydrogen cyanide in air. National Institute for Occupational Safety and Health, Division of Physical Sciences and Engineering, Method Research Branch, Cincinnati, OH. NTIS No PB86-23-6171. *Chandra H, Gupta BN, Ghargava SK, et al. 1980. Chronic cyanide exposure: A biochemical and industrial hygiene study. J Anal Toxicol 4:161-165. *Chandra H, Gupta BN, Mathur N. 1988. Threshold limit value of cyanide: A reappraisal in Indian context. Indian J Environ Protection 8:170-174. *Chen KK, Rose CL. 1952. Nitrite and thiosulfate therapy in cyanide poisoning. J Am Med Assoc 149:113- 119. *Cherryholmes KL, Comils WJ, McDonald DB, et al. 1985. Biological degradation of complex iron cyanides in natural aquatic systems. In: Cardwell RD, Purdy R, Bahner RC, eds. Aquatic Toxicology and Hazard Assessment Seventh Symposium. ASTM STP 854. American Society for Testing and Material, Philadelphia, PA, 502-511. *Cicerone RJ, Zellner R. 1983. The atmospheric chemistry of hydrogen cyanide (HCN). J Geophys Res 88:10689-10696. *Cliff J, Lundquist P, Rosling H, et al. 1986. Thyroid function in a cassava-eating population affected by epidemic spastic paraparesis. Acta Endocrinol (Copenh) 113:523-528. 104 8. REFERENCES *CLPSD. 1989. Contract Laboratory Program Statistical Database. July 12, 1989. *CMR (Chemical Marketing Reporter). 1982. Chemical profile: Hydrogen cyanide. October 11, 1982. New York, NY: Schnell Publishing Co., 62. *CMR (Chemical Marketing Reporter). 1990. Chemical profile: Hydrogen cyanide. June 18, 1990. New York, NY: Schnell Publishing Co., 54. *Cole, RH, Frederick RE, Healy RP, et al. 1984. Preliminary findings of the priority pollutant monitoring project of the nationwide urban runoff program. J Water Pollut Control Fed 56:898-908. *Cotton FA, Wilkinson G. 1980. Advanced inorganic chemistry. A comprehensive text. 4th ed. New York: John Wiley and Sons, 367-369. *CRISP. 1990. Crisp Data Base, National Institutes of Health. July, 1990. *Dahl AR. 1989. The cyanide-metabolizing enzyme rhodanese in rat nasal respiratory and olfactory mucosa. Toxicol Lett 45:199-205. *De Flora S. 1981. Study of 106 organic and inorganic compounds in the Salmonella/microsome test. Carcinogenesis 2:283-298. *De Flora S, Camoirano A, Zanacchi P, et al. 1984. Mutagenicity testing with TA97 and TA102 of 30 DNA- damaging compounds, negative with other Salmonella strains. Mutat Res 134:159-165. *Delange F, Ermans AM. 1971. Role of a dietary goitrogen in the etiology of endemic goiter on Idjwi Island. Am J Clin Nutr 24:1354-1360. *Devlin DJ, Mills JW, Smith RP. 1989a. Histochemical localization of rhodanese activity in rat liver and skeletal muscle. Toxicol Appl Pharmacol 97:247-255. *Devlin DJ, Smith RP, Thron CD. 1989b. Cyanide metabolism in the isolated, perfused, bloodless hindlimbs or liver of the rat. Toxicol Appl Pharmacol 98:338-349. *Dodds C, McKnight C. 1985. Cyanide toxicity after immersion and the hazards of dicobalt edetate. Br Med J 291:785-786. *Doherty PA, Ferm VH, Smith RP. 1982. Congenital malformations induced by infusion of sodium cyanide in the Golden hamster. Toxicol Appl Pharmacol 64:456-464. *Doherty PA, Smith RP, Ferm VH. 1983. Comparison of the teratogenic potential of two aliphatic nitriles in hamsters: Succinonitrile and tetramethylsuccinonitrile. Fundam Appl Toxicol 3:41-48. *Dolzine TW, Esposito GG, Rinehart DS. 1982. Determination of hydrogen cyanide in air by ion chromatography. Anal Chem 54:470-473. *Drawbaugh RB, Marrs TC. 1987. Interspecies differences in rhodanese (thiosulfate sulfurtransferase, EC 2.8.1.1) activity in liver, kidney and plasma. Comp Biochem Physiol 86B:307-310. 105 8. REFERENCES *Drinker P. 1932. Hydrocyanic acid gas poisoning by absorption through the skin. J Ind Hyg 14:1-2. *Dudley HC, Sweeney TR, Miller JW. 1942. Toxicology of acrylonitrile (vinyl cyanide) II: Studies of effects of daily inhalation. J Ind Hyg Toxicol 24:255-258. *Du Pont Chemical Company. 1971. Myocardial infarction, mortality, and sickness absenteeism among employees in the sodium cyanide area of the Memphis Plant [unpublished study]. *Dufour DL. 1988. Dietary cyanide intake and serum thiocyanate levels in Tukanoan indians in Northwest Amazonia. Am J Phys Anthropol 75:205. *Egekeze JO, Ochme FW. 1979. Direct potentiometric method for the determination of cyanide in biological materials. J Anal Toxicol 3:119-124, *El Ghawabi SH, Gaafar MA, El-Saharti AA, et al. 1975. Chronic cyanide exposure: A clinical, radioisotope, and laboratory study. Br J Ind Med 32:215-219. *Ellenhorn MJ, Barceloux DG. 1988. Medical toxicology. Diagnosis and treatment of human poisoning. New York, NY: Elsevier. Engel RR, Delpy DT, Parker D. 1979. The effect of topical potassium cyanide on transcutaneous gas measurements. Birth Defects 15:117-121. *EPA. 1980. Environmental Protection Agency. Water quality criteria documents: Availability. Federal Register 45:79318-79379. *EPA. 1983a. Methods for chemical analysis of water and wastes. Method 335.2. cyanide, total. Environmental Monitoring and Support Laboratory, EPA, Cincinnati, OH. *EPA. 1984. Health effects assessment for cyanide. EPA/540/1-86-011. Response prepared by the Office of Health and Environmental Assessment Environmental Criteria and Assessment Office for the Office of Solid Waste and Emergency Response. *EPA. 1985a. Ambient water quality for cyanide - 1984. EPA Report No 440/5-84-028, Office of Water Regulations and Standards, Criteria and Standards Division, Washington, DC. NTIS PB85-227460. *EPA. 1986a. Integrated Risk Information System (IRIS): Reference dose (RfD) for oral exposure for hydrogen cyanide. Online. (Verification date 8/5/85). Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. *EPA. 1987a. Drinking Water Criteria Document for Cyanide. Prepared by the Office of Health and Environmental Assessment Environmental Criteria and Assessment Office, Cincinnati, OH, for the Office of Drinking Water, Washington, DC. External Review Draft. *EPA. 1987a. Environmental Protection Agency. Extremely hazardous substances list and threshold planning quantities: Emergency planning and release notification requirements. Federal Register 52:13378-13410. 106 8. REFERENCES *EPA. 1987b. Environmental Protection Agency. List (Phase 1) of hazardous constituents for ground-water monitoring. Federal Register 52:25942-25953. *EPA. 1988. Method 9010, 9010a. In: Test methods for evaluating solid waste. SW846. Washington, DC: Office of Solid Waste and Emergency Response, EPA 9010-1 to 9010-15 9010 A-1 to 9010 A-5. *EPA. 1988a. Environmental Protection Agency. Calcium cyanide: Tolerances for residues. Code of Federal Regulations. 40 CFR 180.125. *EPA. 1988b. Environmental Protection Agency. Analysis of clean water act effluent guidelines pollutants. Summary of the chemicals regulated by industrial point source category. Code of Federal Regulations. 40 CFR 400-475. *EPA. 1988c. Environmental Protection Agency. Hydrogen cyanide: Tolerances for residues. Code of Federal Regulations. 40 CFR 180.130. *EPA. 1989a. Interim methods for development of inhalation reference doses. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment. Washington, DC. EPA 600/3-88-066F. *EPA. 1989b. Environmental Protection Agency. Land disposal restrictions for third scheduled wastes: Proposed rule. Federal Register 54:48515-48518. *EPA. 1989c. Environmental Protection Agency. Reportable quantity adjustments: Delisting of ammonium thiosulfate. Federal Register 54:33426-33484. *EPA. 1990a. Summary review of health effects associated with hydrogen cyanide: Health issue assessment. Research Triangle Park, NC: Environmental Criteria and Assessment Office, Office of Health and Environmental Assessment, Office of Research and Development, U.S. Environmental Protection Agency, EPA 600/8-90/002F. *EPA. 1990b. Environmental Protection Agency. National primary and secondary drinking water regulations: Synthetic organic chemicals and inorganic chemicals. Federal Register 55:30370-30371. *Ermans AM, Delange F, Van Der Velden M, et al. 1972. Possible role of cyanide and thiocyanate in the etiology of endemic cretinism. Adv Exp Med Biol 30:455-486. *Ermans AM, Nbulamoko NM, Delange F, et al., eds. 1980. Role of cassava in the etiology of endemic goitre and cretinism. Ottawa, Canada: International Development Research Centre, 1-182. Evans EF, Klinke R. 1982. The effects of intraocochlear cyanide and tetrodotoxin on the properties of single cochlear nerve fibres in the cat. J Physiol 331:385-408. *Fairley A, Linton EC, Wild FE. 1934. The absorption of hydrocyanic acid vapour through the skin with notes on other matters relating to acute cyanide poisoning. J Hyg 34:283-294. *Farooqui MYH, Ahmed AE. 1982. Molecular interaction of acrylonitrile and potassium cyanide with rat blood. Chem Biol Interact 38:145-159. *FEDRIP. 1990. Federal Research in Progress. July 1990. 107 8. REFERENCES *Feldstein M, Klendshoj NC. 1954. The determination of cyanide in biologic fluids by microdiffusion analysis. J Lab Clin Med 44:166-170. *Ferguson HC. 1962. Dilution of dose and acute oral toxicity. Toxicol Appl Pharmacol 4:759-762. *Fiksel J, Cooper C, Eschenroeder A, et al. 1981. Exposure and risk assessment for cyanide. EPA/440/4- 85/008. NTIS PB85-220572. *Finck PA. 1969. Postmortem distribution studies of cyanide: Report of three cases. Med Ann Dist Columbia 38:357-358. *Fogg AG, Alonso RM. 1987. Oxidative amperometric flow injection determination of cyanide at an electrochemically pre-treated glassy carbon electrode. Analyst 112:1071-1072. *Fonong T. 1987. Enzyme method for the spectrophotometric determination of micro-amounts of cyanide. Analyst 112:1033-1035. *Frakes RA, Sharma RP, Willhite CC, et al. 1986. Effect of cyanogenic glycosides and protein content in cassava diets on hamster prenatal development. Fundam Appl Toxicol 7:191-198. *Friedman MA, Staub J. 1976. Inhibition of mouse testicular DNA synthesis by mutagens and carcinogens as a potential simple mammalian assay for mutagenesis. Mutat Res 37:67-76. *Fritz B, Lorenz K, Steinert W, et al. 1982. Laboratory kinetic investigation of the tropospheric oxidation of selected industrial emissions. In: Comm. Eur. Communities, Eur 7624. Phys Chem Behav Atmos Pollut, 192- 202. *FSTRAC. 1990. Summary of state and federal drinking water standards and guidelines. Chemical Communication Subcommittee, Federal-State Toxicology and Regulatory Alliance Committee. *Gaffney JS, Streit GE, Spall WD, et al. 1987. Beyond acid rain - do soluble oxidants and organic toxins interact with SO, and NOy to increase ecosystem effects. Environ Sci Technol 21:519-523. *Ganjeloo A, Isom GE, Morgan RL, et al. 1980. Fluorometric determination of cyanide in biological fluids with p-benzoquinone. Toxicol Appl Pharm 55:103-107. *Gaudy AF, Gaudy ET, Feng YJ, et al. 1982. Treatment of cyanide waste by the extended aeration process. J Water Pollut Control Fed 54:153-164. *Ger J, Chung HM, Yang GY, et al. 1988. A clinical survey of cyanide poisoning in Taiwan [Abstract]. Vet Hum Toxicol 30:377. *Gerhart JM. 1986. Ninety-day oral toxicity study of copper cyanide (CuCN) in Sprague-Dawley Rats. Prepared for The Dynamac Corporation, Rockville, MD by IIT Research Institute, Chicago, IL. IITRI Project No. L06183, Study No. 3. 108 8. REFERENCES Gerhart JM. 1987. Ninety-day oral toxicity study of potassium silver cyanide [KAg(CN),] in Sprague-Dawley rats. Prepared for The Dynamac Corporation, Rockville, MD by IIT Research Institute, Chicago, IL. IITRI Project No. L06183, Study No. 4. *Gettler AO, Baine JO. 1938. The toxicology of cyanide. Am J Med Sci 195:182-198. *Gettler AO, St. George AV. 1934. Cyanide poisoning. Am J Clin Pathol 4:429-437. *Goldfrank LR, Flomenbaum NE, Lewin NA. 1990. Toxicologic emergencies. Norwalk, CT/San Mateo, CA: Appleton & Lange. *Gosselin RE, Hodge HC, Smith RP, et al. 1976. Clinical toxicology of commercial products: Acute poisoning. 4th ed. Baltimore, MD: The Williams & Williams Co., 105-112. *Grandas F, Artieda J, Obeso JA. 1989. Clinical and CT scan findings in a case of cyanide intoxication. Mov Disord 4:188-193. *Gray BH, Porvaznik M, Lee LH. 1986. Cyanide stimulation of tri-n-butyltin mediated hemolysis. J Appl Toxicol 6:263-269. *Great Lakes Water Quality Board. 1983. An inventory of chemical substances identified in the Great Lakes ecosystem. Vol. 1. Summary Report to the Great Lakes Water Quality Board. Windsor Ontario, Canada 195. *Greim H. 1990. Toxicological evaluation of emission from modern municipal waste incinerators. Chemosphere 20:317-331. *Gross DW. 1986. Treatment technologies for hazardous wastes part IV. A review of alternative treatment processes for metal-bearing hazardous waste streams. J Air Pollut Control Assoc 36:603-614. Hansen BA, Dekker EE. 1976. Inactivation of bovine liver 2-Keto-4-hydroxyglutarate aldolase by cyanide in the presence of aldehydes. Biochemistry 15:2912-2917. *Hargis KM, Tillery MI, Ettinger HJ, et al. 1986. Industrial hygiene study of a true in-situ oil shale retorting facility. Am Ind Hyg Assoc J 47:455-464. *Hartung R. 1982. Cyanides and nitriles. In: Clayton GD, Clayton FE, eds. Patty’s industrial hygiene and toxicology. Vol IIC, 3rd ed. New York, NY: John Wiley and Sons, 4845-4900. *Hawley GG. 1981. The condensed chemical dictionary. 10 ed. New York, NY: Van Nostrand Reinhold Co., 106, 180-181, 275, 294-295, 542, 847-848, 924, 937-938, 1108. *Haymaker W, Ginzler AM, Ferguson RL. 1952. Residual neuropathological effects of cyanide poisoning: A study of the central nervous system of 23 dogs exposed to cyanide compounds. The Military Surgeon 3:231-246. *HAZDAT. 1992. Agency for Toxic Substances and Disease Registry (ATSDR), Atlanta, GA. October 30, 1992. 109 8. REFERENCES *Hertting GO, Kraupp E, Schnetz E, et al. 1960. [Investigation about the consequences of a chronic administration of acutely toxic doses of sodium cyanide to dogs.] Acta Pharmacol Toxicol 17:27-43. [German] *Heuser SG, Scudmore KA. 1969. Determination of fumigant residues in cereals and other foodstuffs: A multidetection scheme for gas chromatography of solvent extract. J Sci Food Agric 20:566-572. *Higgins TE, Desher DP. 1988. Metal finishing and processing. J Water Pollut Control Fed 60:904-909. *Higgins EA, Fiorca V, Thomas AA, et al. 1972. Acute toxicity of brief exposures to HF, HCI, NO? and HCN with and without CO. Fire Technol 8:120-130. *Himwich WA, Saunders JP. 1948. Enzymatic conversion of cyanide to thiocyanate. Am J Physiol 153:348- 354. *Hirano A, Levine S, Zimmerman HM. 1967. Experimental cyanide encephalopathy: Electron microscopic observations of early lesions in white matter. J Neuropathol Exp Neurol 26:200-213. *Hirano A, Levine S. Zimmerman HM. 1968. Remyelination in the central nervous system after cyanide intoxication. J Neuropathol Exp Neurol 27:234-245. *Honig DH, Hockridge ME, Gould RM, et al. 1983. Determination of cyanide in soybeans and soybean products. J Agric Food Chem 31:272-275. *Howard JW, Hanzal RF. 1955. Chronic toxicity for rats of food treated with hydrogen cyanide. Agricultural and Food Chemistry 3:325-329. *Howlett WP, Brubaker GR, Mlingi N, et al. 1990. Konzo, an epidemic upper motor neuron disease studied in Tanzania. Brain 113:223-235. *HSDB (Hazardous Substance Data Bank). 1990. Online: July 1990 and August 1990. *Huiatt JL. 1985. Cyanide from mineral processing: Problems and research needs. Conf. Cyanide and Environment, Tuscon, AZ, December 1984. Published by Geotechnical Engineering Program, Colorado State University, Fort Collins, CO 65-81. *Ibrahim MZ, Briscoe PB, Bayliss OB, et al. 1963. The relationship between enzyme activity and neuroglia in the prodromal and demyelinating stages of cyanide encephalopathy in the rat. J Neurol Neurosurg Psychiatry 26:479-486. *IRIS. 1992. Integrated Risk Information System. U.S. Environmental Protection Agency, Office of Health and Environmental Assessment, Environmental Criteria and Assessment Office, Cincinnati, OH. January 1, 1992. *Isom GE, Way JL. 1974a. Cyanide intoxication: Protection with cobaltous chloride. Toxicol Appl Pharmacol 24:449-456. *Isom GE, Way JL. 1974b. Effect of oxygen on cyanide intoxication. VI. Reactivation of cyanide-inhibited glucose metabolism. J Pharmacol Exp Ther 189:235-243. 110 8. REFERENCES *Isom GE, Liu DHW, Way JL. 1975. Effect of sublethal doses of cyanide on glucose catabolism. Biochem Pharmacol 24:871-875. *Isom GE, Burrows GE, Way JL. 1982. Effect of oxygen on the antagonism of cyanide intoxication-cytochrome oxidase, in vivo. Toxicol Appl Pharmacol 65:250-256. *Jacangelo JG, Patania NL, Reagan KM, et al. 1989. Ozonation: Assessing its role in the formation and control of disinfection by-products. J Am Water Works Assoc 81:74-84. *Jackson LC. 1988. Behavioral effects of chronic sublethal dietary cyanide in an animal model: Implications for humans consuming cassava (Manihot esculenta). Hum Biol 60:597-614. *Jackson LC, Chandler JP, Jackson RT. 1986. Inhibition and adaptation of red cell glucose-6-phosphate dehydrogenase (G6PD) in vivo to chronic sublethal dietary cyanide in an animal model. Hum Biol 58:67-77. *Jaramillo, M., DeZafra RL, Barrett J, et al. 1989. Measurements of stratospheric hydrogen cyanide and McMurdo Station, Antarctica: Further evidence of winter stratospheric subsidence? J Geophys Res 94:16,773- 16,7717. *Jenks WR. 1979. Cyanides. In: Grayson, M, ed. Kirk-Othmer encyclopedia of chemical technology. New York, NY: John Wiley and Sons, Inc., 307-334. Johnson JD, Isom GE. 1985. The oxidative disposition of potassium cyanide in mice. Toxicology 37:215-224. *Johnson JD, Isom GE. 1987. Peroxidation of brain lipids following cyanide intoxication in mice. Toxicology 46:21-28. *Johnson JD, Meisenheimer TL, Isom GE. 1986. Cyanide-induced neurotoxicity: Role of neuronal calcium. Toxicol Appl Pharmacol 84:464-469. Johnson JD, Conroy WG, Isom GE. 1987. Effect of pentobarbital on cyanide-induced tremors in mice and calcium accumulation in PC12 cells. Biochem Pharmacol 36:1747-1749. *Kadushin FS, Bronstein AC, Riddle MW, et al. 1988. Cyanide induced parkinsonism: Neuropsychological and radiological findings [Abstract]. Vet Hum Toxicol 30:359. *Kanthasamy AG, Maduh EU, Peoples RW, et al. 1991a. Calcium mediation of cyanide-induced catecholamine release: Implications for neurotoxicity. Toxicol Appl Pharmacol 110:275-282. *Kanthasamy AG, Borowitz JL, Isom GE. 1991b. Cyanide-induced increases in plasma catecholamines: Relationship to acute toxicity. Neurotoxicology 12:777-784. *Kato T, Kameyama M, Nakamura S, et al. 1985. Cyanide metabolism in motor neuron disease. Acta Neurol Scand 72:151-156. Katsumata Y, Sato K, Yada S, et al. 1983. Kinetic analysis of anaerobic metabolism in rats during acute cyanide poisoning. Life Sci 33:151-155. 11 8. REFERENCES *Keniston RC, Cabellon S, Yarbrouch KS. 1987. Pyridoxal 5"-phosphate as an antidote for cyanide, spermine, gentamicin, and dopamine toxicity: An in vivo rat study. Toxicol Appl Pharmacol 88:433-441. *Khandekar JD, Edelman H. 1979. Studies of amygdalin (laetrile) toxicity in rodents. J Am Med Assoc 242:169-171. *Kirk RL, Stenhouse NS. 1953. Ability to smell solutions of potassium cyanide. Nature 171:698-699. *Kirk M, Kulig K, Rumack BH. 1989. Methemoglobin and cyanide kinetics in smoke inhalation [Abstract]. Vet Hum Toxicol 31:353. *Klecka GM, Landi LP, Bodner KM. 1985. Evaluation of the OECD activated sludge, respiration inhibition test. Chemosphere. 14:1239-1251. *Klimmek R, Roddewig C, Fladerer H, et al. 1983. Effects of 4-dimethylaminophenol, Co,EDTA, or NaNO, on cerebral blood flow and sinus blood homeostasis of dogs in connection with acute cyanide poisoning. Toxicology 26:143-154. *Kopfler FC, Melton RG, Mullaney JL, et al. 1977. Human exposure to water pollutants. Adv Environ Sci Technol 8:419-433. *Kopp S, Kisling G, Paulson D, et al. 1989. Cardiac actions of cadmium, potassium cyanide and carbonyl cyanide m-chlorophenylhydrazone [Abstract]. FASEB J 3:A-251. *Krasner SW, McGuire MJ, Jacangelo JG, et al. 1989. The occurrence of disinfection by-products in U.S. drinking water. J Am Water Works Assoc 81:41-53. *Kreutler PA, Varbanov V, Goodman W, et al. 1978. Interactions of protein deficiency, cyanide, and thiocyanate on thyroid function in neonatal and adult rats. Am J Clin Nutr 31:282-289. *Kruszyna R, Kruszyna H, Smith RP. 1982. Comparison of hydroxylamine, 4-dimethylaminophenol and nitrite protection against cyanide poisoning in mice. Arch Toxicol 49:191-202. *Kushi A, Matsumoto T, Yoshida D. 1983. Mutagen from the gaseous phase of protein pyrolyzate. Agric Biol Chem 47:1979-1982. *Landahl HD, Herrmann RG. 1950. Retention of vapors and gases in the human nose and lung. Arch Ind Hyg Occup Med 1:36-45. *Lasch EE, El Shawa R. 1981. Multiple cases of cyanide poisoning by apricot kernels in children from Gaza. Pediatrics 68:5-7. *Lessell S. 1971. Experimental cyanide optic neuropathy. Arch Ophthalmol 86:194-204. *Levin BC, Paabo M, Gurman JL, et al. 1987. Effect of exposure to single or multiple combinations of the predominant toxic gases and low oxygen atmospheres produced in fires. Fundam Appl Toxicol 9:236-250. 112 8. REFERENCES *Levine S. 1969. Experimental cyanide encephalopathy: Gradients of susceptibility in the corpus callosum. J Neuropathol Exp Neurol 26:214-222. *Levine S, Stypulkowski W. 1959a. Experimental cyanide encephalopathy. Arch Pathol 67:306-323. *Levine S, Stypulkowski W. 1959b. Effect of ischemia on cyanide encephalopathy. Neurology 9:407-411. *Lewis TR, Anger WK, Te Vault RK. 1984. Toxicity evaluation of sub-chronic exposures to cyanogen in monkeys and rats. J Environ Pathol Toxicol Oncol 5:151-163. *Liebowitz D, Schwartz H. 1948. Cyanide poisoning: Report of a case with recovery. Am J Clin Pathol 18:965-970. *Litovitz TL, Larkin RF, Myers RA. 1983. Cyanide poisoning treated with hyperbaric oxygen. Am J Emerg Med 1:94-101. *Ludzack FJ, Moore WA, Krieger HL, et al. 1951. Effect of cyanide on biochemical oxidation in sewage and polluted water. Sewage Ind Wastes 23:1298-1307. *Lundquist P, Sorbo B. 1989. Rapid determination of toxic cyanide concentrations in blood. Clin Chem 35:617-619. Lundquist P, Rammer L, Sorbo B. 1989. The role of hydrogen cyanide and carbon monoxide in fire casualties: A prospective study. Forensic Sci Int 43:9-14. *Maduh EU, Johnson JD, Ardelt BK, et al. 1988. Cyanide-induced neurotoxicity: Mechanisms of attenuation by chlorpromazine. Toxicol Appl Pharmacol 96:60-67. *Maduh EU, Borowitz JL, Isom GE. 1990a. Cyanide-induced alteration of cytosolic pH: Involvement of cellular hydrogen ion handling processes. Toxicol Appl Pharmacol 106:201-208. *Maduh EU, Turek JJ, Borowitz JL, et al. 1990b. Cyanide-induced neurotoxicity: Calcium mediation of morphological changes in neuronal cells. Toxicol Appl Pharmacol 103:214-221. *Makene WJ, Wilson J. 1972. Biochemical studies in Tanzanian patients with ataxic tropical neuropathy. J Neurol Neurosurg Psychiatry 35:31-33. *Malaney GW, Sheets WD, Quillin R. 1959. Toxic effects of metallic ions on sewage microorganisms. Sewage Ind Wastes 31:1909-1915. *Maliszewski TF, Bass DE. 1955. ‘True’ and ‘apparent’ thiocyanate in body fluids of smokers and nonsmokers. J Appl Physiol 8:289-291. *Malone KE, Koepsell TD, Daling JR, et al. 1987. Chronic lymphocytic leukemia in relation to toxic substance exposure [Abstract]. Am J Epidemiol 126:763. 113 8. REFERENCES *Maseda C, Matsubara K, Shiono H. 1989. Improved gas chromatography with electron-capture detection using a reaction pre-column for the determination of blood cyanide: a higher content in the left ventricle of fire victims. J Chromatogr 82:319-327. *Matijak-Schaper M, Alarie Y. 1982. Toxicity of carbon monoxide, hydrogen cyanide and low oxygen. Journal of Combustion Toxicology 9:21-61. *McMahon T, Bimbaum L. 1990. Age-related changes in biotransformation and toxicity of potassium cyanide (KCN) in male CS7BL/6N mice [Abstract]. In: Proceedings of the 29th annual meeting of the Society of Toxicology 29th Annual Meeting, Miami Beach, FL. *McMillan DE, Svoboda AC. 1982. The role of erythrocytes in cyanide detoxification. J Pharmacol Exp Ther 221:37-42. *McNemey JM, Schrenk HH. 1960. The acute toxicity of cyanogen. Am Ind Hyg Assoc J 21:121-124. *Meeussen JCL, Temminghoff EJM, Keizer MG, et al. 1989. Spectrophotometric determination of total cyanide, iron - cyanide complexes, free cyanide and thiocyanate in water by a continuous-flow system. Analyst (London) 114:959-963. *Mengel K, Kramer W, Isert B, et al. 1989. Thiosulphate and hydroxocobalamin prophylaxis in progressive cyanide poisoning in guinea-pigs. Toxicology 54:335-342. *Ministry of Health, Mozambique. 1984. Mantakassa: An epidemic of spastic paraparesis associated with chronic cyanide intoxication in a cassava staple area of Mozambique. 1. Epidemiology and clinical and laboratory findings in patients. Bull WHO 62:477-484. *Monekosso GL, Wilson J. 1966. Plasma thiocyanate and vitamin B,, in Nigerian patients with degenerative neurological disease. Lancet 14:1062-1064. *Money GL. 1958. Endemic neuropathies in the Epe district of southern Nigeria. West Aft Med J 7:58-62. *Moore SJ, Norris JD, Ho IK, et al. 1986. The efficacy of a-ketoglutaric acid in the antagonism of cyanide intoxication. Toxicol Appl Pharmacol 82:40-44. *Morgan RL, Way JL. 1980. Fluorometric determination of cyanide in biological fluids with pyridoxal. J Anal Toxicol 4:78-81. *Mushett CW, Kelley KL, Boxer GE, et al. 1952. Antidotal efficacy of vitamin B,, (hydroxo-cobalamin) in experimental cyanide poisoning. Proc Soc Exp Biol Med 81:234-247. *Myers VB. 1983. Remedial activities at the Miami Drum site, Florida. Natl. Conf. Manage. Uncontrolled Hazard. Waste Sites 354-357. NAS/NRC. 1989. Biologic markers in reproductive toxicology. National Academy of Sciences/National Research Council. Washington, DC: National Academy Press, 15-35. 114 8. REFERENCES *NATICH. 1992. National Air Toxics Information Clearinghouse, Office of Air Quality Planning and Standards, U.S. Environmental Protection Agency, State and Territorial Air Pollution Program Administrators, Association of Local Air Pollution Control Officials. *NIOSH. 1976. National Institute for Occupational Safety and Health. Health Hazard Evaluation Report No. 74-129-268, U.S. Dept. of Health, Education, and Welfare, Center for Disease Control, NIOSH, Cincinnati, OH. *NIOSH. 1978. National Institute for Occupational Safety and Health. Health Hazard Evaluation Report No. 77-88-457), U.S. Dept. of Health, Education, and Welfare, Center for Disease Control, NIOSH, Cincinnati, OH. *NIOSH. 1982. National Institute for Occupational Safety and Health. In-depth survey report of american airlines plating facility, NIOSH, Cincinnati, OH. PB83-187799, Springfield, VA. *NIOSH. 1986. National Institute for Occupational Safety and Health. Morbidity and Mortality Weekly Supplement 35:198S. *NIOSH. 1989a. National Institute for Occupational Safety and Health. Occupational Exposure Survey (NOES), March 29, 1989, NIOSH, Cincinnati, OH 13, 47, 49. *NIOSH. 1989b. National Institute for Occupational Safety and Health. NIOSH Manual of Analytical Methods. Method 7904. 3rd ed., NIOSH Publication No. 84-100, Cincinnati, OH: U.S. Dept. of Health and Human Services, Centers for Disease Control, NIOSH 7904-1 to 7904-4. *NIOSH. 1990. National Institute for Occupational Safety and Health. NIOSH pocket guide to chemical hazards. U.S. Department of Health and Human Services. DHHS (NIOSH) publication No. 90-117. *Nonomura M. 1987. Indirect determination of cyanide compounds by ion chromatography with conductivity measurement. Anal Chem 59:2073-2076. *NTP. 1990. Chemical status report produced from NTP chemtrack system. National Toxicology Program, Division of Toxicology Research and Testing. *QObidoa O, Obasi SC. 1991. Coumarin compounds in cassava diets: 2 health implications of scopoletin in gari. Plant Food for Human Nutrition 41: 283-289. *Q’Flaherty EJ, Thomas WC. 1982. The cardiotoxicity of hydrogen cyanide as a component of polymer pyrolysis smokes. Toxicol Appl Pharmacol 63:373-381. *Ohio River Valley Water Sanitation Commission. 1982. Assessment of the Water Quality Conditions: Ohio River Mainstream 1980-81. Ohio River Valley Water Sanit. Comm., Cincinnati, OH. *Ohno T. 1989. Spectrophotometric determination of total cyanide in surface waters following ultra-violet- induced photodecomposition. Analyst (London) 114:857-858. *Ohya T, Kanno S. 1987. Formation of cyanogen chloride during the chlorination of water containing aromatic compounds and ammonium ion. J Pharm Sci 76(11). 115 8. REFERENCES *Okoh PN. 1983. Excretion of “C-labeled cyanide in rats exposed to chronic intake of potassium cyanide. Toxicol Appl Pharmacol 70:335-339. *OSHA. 1989. Occupational Safety and Health Administration. Air contaminants: Final rule. Federal Register 54:2332-2925. *Osuntokun BO. 1968. An ataxic neuropathy in Nigeria: A clinical, biochemical and electrophysiological study. Brain 91:215-248. *Osuntokun BO. 1972. Chronic cyanide neurotoxicity and neuropathy in Nigerians. Plant Foods for Human Nutrition 2:215-266. *Osuntokun BO. 1980. A degenerative neuropathy with blindness and chronic cyanide intoxication of dietary origin: The evidence in the Nigerians. In: Smith RL and Bababunmi EA, eds. Toxicology in the tropics. London: Taylor and Francis, 16-52. *Osuntokun BO, Monekosso GL, Wilson J. 1969. Relationship of a degenerative tropical neuropathy to diet report of a field survey. Br Med J 1:547-550. Owasoyo JO, Iramain CA. 1980. Acetylcholinesterase activity in rat brain: Effect of acute cyanide intoxication. Toxicol Lett 6:1-3. Painter RB, Howard R. 1982. The HeLa DNA-synthesis inhibition test as a rapid screen for mutagenic carcinogens. Mutat Res 92:427-437. *Palmer IS, Olson OE. 1979. Partitial prevention by cyanide of selenium poisoning in rats. Biochem Biophys Res Comm 90:1379-1386. *Patel MN, Yim GKW, Isom GE. 1992. Blockade of N-methyl-D-aspartate receptors prevents cyanide-induced neuronal injury in primary hippocampal cultures. Toxicol Appl Pharmacol 115:124-129. *Peden NR, Taha A, McSorley PD, et al. 1986. Industrial exposure to hydrogen cyanide: Implications for treatment. Br Med J 293:538. *Persson SA, Cassel G, Sellstrom A. 1985. Acute cyanide intoxication and central transmitter systems. Fund Appl Toxicol 5:5150-5159. *Pettet AEJ, Mills EV. 1954. Biological treatment of cyanides with and without sewage. J Appl Chem 4:434- 444. *Pettigrew AR, Fell GS. 1972. Simplified colorimetric determination of thiocyanate in biological fluid and its application of investigation of toxic amblyopias. Clin Chem 18:996-1000. *Pettigrew AR, Fell GS. 1973. Microdiffusion method for estimation of cyanide in whole blood and its application to the study of conversion of cyanide to thiocyanate. Clin Chem 19:466-471. *Philbrick DJ, Hopkins JB, Hill DC, et al. 1979. Effects of prolonged cyanide and thiocyanate feeding in rats. J Toxicol Environ Health 5:579-592. 116 8. REFERENCES *Poitrast BJ, Keller WC, Elves RG. 1988. Estimation of chemical hazards in breast milk. Aviat Space Environ Med 59:A87-A92. *Potter AL. 1950. The successful treatment of two recent cases of cyanide poisoning. Br J Ind Med 7:125-130. *Purser DA, Grimshaw P, Bemrill KR. 1984. Intoxication by cyanide in fires: A study in monkeys using polyacrylonitrile. Arch Environ Health 39:394-400. *Raef SF, Characklis WG, Kessick MA, et al. 1977. Fate of cyanide and related compounds in aerobic microbial systems--II. Microbial degradation. Water Res 11:485-492. *Rawlings GD, Samfield M. 1979. Textile plant waste water toxicity. Environ Sci Technol 13:160-164. *Richards DJ, Shieh WK. 1989. Anoxic-oxic activated-sludge treatment of cyanides and phenols. Biotechnol Bioeng 33:32-38. *Rieders F. 1971. Noxious gases and vapors I: Carbon monoxide, cyanides, methemoglobin, and sulfhemoglobin. In: DePalma JR, ed. Drill’s pharmacology in medicine, 4th ed. New York, NY: McGraw-Hill Book Company, 1180-1205. *Robinson CP, Baskin SI, Franz DR. 1985a. The mechanisms of action of cyanide on the rabbit aorta. J Appl Toxicol 5:372-377. *Robinson CP, Baskin SI, Visnich N Jr., et al. 1985b. The effects of cyanide and its interactions with norepinephrine on isolated aorta strips from the rabbit, dog, and ferret. Toxicology 35:59-72. *Rocklin RD, Johnson DL. 1983. Determination of cyanide, sulfide, iodide, and bromide by ion chromatography with electrochemical detection. Anal Chem 55:4-7. *Rohmann SO, Miller RL, Scott EA, et al. 1985. Tracing a river’s toxic pollution: A case study of the Hudson. McCook AS, ed. New York, NY, Inform 154. *Rosenberg NL, Myers JA, Martin WRW. 1989. Cyanide-induced parkinsonism clinical MRI and 6 fluorodopa Fd positron emission tomography pet studies. Neurology 39:142-144. *Rosling H. 1987. Cassava toxicity and food security. Prepared for UNICEF African Household Food Security Program. Uppsala, Sweden: Tryck kontakt. 1-40. *Rosling H. 1988. Cassava toxicity and food security. A report for UNICEF African household food security programme. 2nd ed. Uppsala, Sweden: Tryck kontakt, 1-40. *Rubio R, Sanz J, Rauret G. 1987. Determination of cyanide using a microdiffusion technique and potentiometric measurement. Analyst 112:1705-1708. *Rutkowski JV, Roebuck BD, Smith RP. 1985. Effects of protein-free diet and food deprivation on hepatic rhodanese activity, serum proteins and acute cyanide lethality in mice. J Nutr 115:132-137. *Sandberg CG. 1967. A case of chronic poisoning with potassium cyanide? Acta Med Scand 181:233-236. 17 8. REFERENCES *Sano A, Takezawa M, Takitani S. 1989. Spectrofluorometric determination of cyanide in blood and urine with naphthalene-2,3-dialdehyde and taurine. Analytica Chimica Acta 225:351-358. *Sax NI. 1984. Dangerous properties of industrial materials. 6th ed. New York, NY: Van Nostrand Reinhold Co., 825. *Sax NI, Lewis RD, eds. 1987. Hawley’s condensed chemical dictionary. 11th ed. New York, NY: Van Nostrand Reinhold Co., 203, 954, 1057. *Schneider JF, Westley J. 1969. Metabolic interrelations of sulfur in proteins, thiosulfate, and cystine. J Biol Chem 244:5735-5744. *Schubert J, Brill WA. 1968. Antagonism of experimental cyanide toxicity in relation to the in vivo activity of cytochrome oxidase. J Pharmacol Exp Ther 162:352-359. *Schwartz C, Morgan RL, Way LM, et al. 1979. Antagonism of cyanide intoxication with sodium pyruvate. Toxicol Appl Pharmacol 50:437-441. *Scott JS. 1985. An overview of cyanide treatment methods for gold mill effluents. Conf. Cyanide and Environment, Tuscon, AZ, December 1984. Published by Geotechnical Engineering Program, Colorado State University, Fort Collins, CO, 307-330. *Scrivner NC, Bennett KE, Pease RA, et al. Chemical fate of injected wastes. Ground Water Monit Rev 6:53- 58. *Sheehy M, Way JL. 1968. Effect of oxygen on cyanide intoxication. III. Mithridate. J Pharmacol Exp Ther 161:163-168. *Shivaraman N, Kumaran P, Pandey RA, et al. 1985. Microbial degradation of thiocyanate, phenol and cyanide in a completely mixed aeration system. Environ Pollut, Ser A 39:141-150. *Singh JD. 1981. The teratogenic effects of dietary cassava on the pregnant albino rat: A preliminary report. Teratology 24:289-291. *Singh BM, Coles N, Lewis P, et al. 1989. The metabolic effects of fatal cyanide poisoning. Postgrad Med J 65:923-925. *Sklarew DS, Hayes DJ. 1984. Trace nitrogen-containing species in the offgas from 2 oil shale retorting processes. Environ Sci Technol 18:600-603. *Smyth HF, Carpenter CP, Weil CS, et al. 1969. Range-finding toxicity data: List VII. Am Ind Hyg Assoc J 30:470-476. *SRI (Stanford Research Institute). 1990. 1990 directory of chemical producers. United States of America, SRI International, Menlo Park, CA, 547, 924, 958. *Stadelmann W. 1976. Content of hydrocyanic acid in stone fruit juices. Fluess Obst 43:45-47. 118 8. REFERENCES *State of Kentucky. 1986. New or modified sources emitting toxic air pollutants. Natural Resources and Environmental Protection Cabinet, Department for Environmental Protection, Division of Air Pollution (Proposed Regulation). 401 KAR 63:022. *Streicher E. 1951. Toxicity of colchicine, di-isopropyl fluorophosphate, intocostrin, and potassium cyanide in mice at 4 degrees C. Proc Soc Exp Biol Med 76:536-538. *Stutz DR, Janusz SJ. 1988. Hazardous materials injuries: A handbook for pre-hospital care. 2nd ed. Beltsville, MD: Bradford Communications Corporation. *Sylvester DM, Holmes RK, Sander C, et al. 1982. Interference of thiosulfate with potentiometric analysis of cyanide in blood and its elimination. Toxicol Appl Pharmacol 65:116-121. *Sylvester DM, Hayton WL, Morgan RL, et al. 1983. Effects of thiosulfate on cyanide pharmacokinetics in dogs. Toxicol Appl Pharmacol 69:265-271. *ten Berge WF, Zwart A, Appelman LM. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. Journal of Hazardous Materials 13:301-309. *Tewe OO, Maner JH. 1980. Cyanide, protein and iodine interactions in the performance, metabolism and pathology of pigs. Res Vet Sci 29:271-276. *Tewe OO, Maner JH. 1981a. Long-term and carry-over effect of dietary inorganic cyanide (KCN) in the life cycle performance and metabolism of rats. Toxicol Appl Pharmacol 58:1-7. *Tewe OO, Maner JH. 1981b. Performance and pathophysiological changes in pregnant pigs fed cassava diets containing different levels of cyanide. Res Vet Sci 30:147-151. *Tewe OO, Maner JH. 1982. Cyanide, protein and iodine interactions in the performance and metabolism of rats. J Environ Pathol Toxicol Oncol 6:69-77. Thomas RG. 1982. Volatilization from water. In: Lyman WIJ, et al. ed. Handbook of chemical property estimation methods: Environmental behavior of organic compounds. New York, NY: McGraw-Hill Book Co., 15-16. *Thomas TA, Brooks JW. 1970. Accidental cyanide poisoning. Anaesthesia 25:110-114. *Toida T, Togawa T, Tanabe S, et al. 1984. Determination of cyanide and thiocyanate in blood plasma and red cells by high-performance liquid chromatography with fluorometric detection. J Chromatogr 308:133-141. *Towill LE, Drury JS, Whitfield BL, et al. 1978. Reviews of the environmental effects of pollutants. V. Cyanide. EPA Health Effects Research Laboratory, Office of Research and Development, Cincinnati, OH. NTIS PB28-9920. *Trapp WG. 1970. Massive cyanide poisoning with recovery: a Boxing-day story. Can Med Assoc J 102:517. *TRI88. 1990. Toxics Release Inventory 1988. Office of Toxic Substances, U.S. Environmental Protection Agency, Washington, DC. 119 8. REFERENCES *Tucker SP, Carson GA. 1985. Deactivation of hazardous chemical wastes. Environ Sci Technol 19:215-220. *Ukhun ME, Dibie EN. 1989. Cyanide content of cassava mash and gari flour and influence of water activity a-w during storage. Bull Environ Contam Toxicol 42:548-552. *U.S.D.C. 1985. United States Department of Commerce. U.S. General Imports and Imports for Consumption. FT135, USDC, Washington, DC, 2-66. Uitti RJ, Rajput AH, Ashenhurst EM, et al. 1985. Cyanide-induced parkinsonism: A clinicopathologic report. Neurology 35:921-925. *Valade MP. 1952. [Central nervous system lesions in chronic experimental poisoning with gaseous hydrocyanic acid). Bull Acad Natl Med (Paris) 136:280-225. (French) *VanderLaan WP, Bissell A. 1946. Effects of propylthiouracil and of potassium thiocyanate on the uptake of iodine by the thyroid gland of the rat. Endocrinology 39:157-160. *Venkataramani ES, Ahlert RC, Corbo P. 1984. Biological treatment of landfill leachates. CRC Crit Rev Environ Control 14:333-376. *Vick JA, Froehlich HL. 1985. Studies of cyanide poisoning. Arch Int Pharmacodyn 273:314-322. *Vogel SN, Sultan TR, Ten Eyck RP. 1981. Cyanide poisoning. Clin Toxicol 18:367-383. *Walton DC, Witherspoon MG. 1926. Skin absorption of certain gases. J Pharmacol Exp Ther 26:315-324. *Way JL. 1984. Cyanide intoxication and its mechanism of antagonism. Ann Rev Pharmacol Toxicol 24:451- 481. *Way JL, Burrows G. 1976. Cyanide intoxication: Protection with chlorpromazine. Toxicol Appl Pharmacol 36:93-97. *Weast RC, ed. 1985. CRC Handbook of Chemistry and Physics. 66th ed. Boca Raton, FL: CRC Press, Inc., B-82, B-93, B-95, B-100, B-127, B-142. *Westley AM, Westley J. 1989. Voltammetric determination of cyanide and thiocyanate in small biological samples. Anal Biochem 181:190-194. *Wexler J, Whittenberger JL, Dumke PR. 1947. The effect of cyanide on the electrocardiogram of man. Am Heart J 34:163-173. *Willhite CC. 1981. Malformations induced by inhalation of acetonitrile vapors in the golden hamster [Abstract]. Teratology 23:69A *Willhite CC. 1982. Congenital malformations induced by laetrile. Science 215:1513-1515. *Willhite CC, Smith RP. 1981. The role of cyanide liberation in the acute toxicity of aliphatic nitriles. Toxicol Appl Pharmacol 59:589-602. 120 8. REFERENCES *Wilson J. 1965. Leber’s hereditary optic atrophy: A possible defect of cyanide metabolism. Clin Sci 29:505- 515, *Wilson J. 1983. Cyanide in human disease: A review of clinical and laboratory evidence. Fundam Appl Toxicol 3:397-399. *Windholz M, ed. 1983. The Merck index. 10th ed. Rahway, NJ: Merck and Co., Inc., 229, 385, 696, 1100, 1104, 1233. *Wood JL, Cooley SL. 1955. Detoxication of cyanide by cystine. J Biol Chem 218:449-457. *Worthing CR, ed. 1987. The pesticide manual. 8th ed. Thornton Heath, UK: British Crop Protection Council, 467. *Yamamoto H. 1989. Hyperammonemia, increased brain neutral and aromatic amino acid levels, and encephalopathy induced by cyanide in mice. Toxicol Appl Pharmacol 99:415-420. *Yamamoto K, Yamamoto Y, Hattori H, et al. 1982. Effects of routes of administration on the cyanide concentration distribution in the various organs of cyanide-intoxicated rats. Tohoku J Exp Med 137:73-78. *Yoo KP, Lee SY, Lee WH. 1986. Ionization and Henry's Law constants for volatile, weak electrolyte water pollutants. Korean J Chem Eng 3:67-72. *Young DR. 1978. Priority pollutants in municipal wastewaters. Annu Rep South Calif Coastal Water Res Proj, 103-112. Zhu Z, Fang Z. 1987. Spectrophotometric determination of total cyanide in waste waters in a flow-injection system with gas-diffusion separation and pre-concentration. Anal Chim Acta 198:25-36. 121 9. GLOSSARY Acute Exposure -- Exposure to a chemical for a duration of 14 days or less, as specified in the Toxicological Profiles. Adsorption Coefficient (K,) -- The ratio of the amount of a chemical adsorbed per unit weight of organic carbon in the soil or sediment to the concentration of the chemical in solution at equilibrium. Adsorption Ratio (Kd) -- The amount of a chemical adsorbed by a sediment or soil (i.e., the solid phase) divided by the amount of chemical in the solution phase, which is in equilibrium with the solid phase, at a fixed solid/solution ratio. It is generally expressed in micrograms of chemical sorbed per gram of soil or sediment. Bioconcentration Factor (BCF) -- The quotient of the concentration of a chemical in aquatic organisms at a specific time or during a discrete time period of exposure divided by the concentration in the surrounding water at the same time or during the same period. Cancer Effect Level (CEL) -- The lowest dose of chemical in a study, or group of studies, that produces significant increases in the incidence of cancer (or tumors) between the exposed population and its appropriate control. Carcinogen -- A chemical capable of inducing cancer. Ceiling Value -- A concentration of a substance that should not be exceeded, even instantaneously. Chronic Exposure -- Exposure to a chemical for 365 days or more, as specified in the Toxicological Profiles. Developmental Toxicity -- The occurrence of adverse effects on the developing organism that may result from exposure to a chemical prior to conception (either parent), during prenatal development, or postnatally to the time of sexual maturation. Adverse developmental effects may be detected at any point in the life span of the organism. Embryotoxicity and Fetotoxicity -- Any toxic effect on the conceptus as a result of prenatal exposure to a chemical; the distinguishing feature between the two terms is the stage of development during which the insult occurred. The terms, as used here, include malformations and variations, altered growth, and in utero death. EPA Health Advisory -- An estimate of acceptable drinking water levels for a chemical substance based on health effects information. A health advisory is not a legally enforceable federal standard, but serves as technical guidance to assist federal, state, and local officials. Immediately Dangerous to Life or Health (IDLH) -- The maximum environmental concentration of a contaminant from which one could escape within 30 min without any escape-impairing symptoms or irreversible health effects. Intermediate Exposure -- Exposure to a chemical for a duration of 15-364 days, as specified in the Toxicological Profiles. Immunologic Toxicity -- The occurrence of adverse effects on the immune system that may result from exposure to environmental agents such as chemicals. In Vitro -- Isolated from the living organism and artificially maintained, as in a test tube. 122 9. GLOSSARY In Vivo -- Occurring within the living organism. Lethal Concentration; q, (LC,,) -- The lowest concentration of a chemical in air which has been reported to have caused death in humans or animals. Lethal Concentration, (LCs) -- A calculated concentration of a chemical in air to which exposure for a specific length of time is expected to cause death in 50% of a defined experimental animal population. Lethal Dosey, (LDyo) -- The lowest dose of a chemical introduced by a route other than inhalation that is expected to have caused death in humans or animals. Lethal Dose, (LDsg) -- The dose of a chemical which has been calculated to cause death in 50% of a defined experimental animal population. Lethal Time, (LTg) -- A calculated period of time within which a specific concentration of a chemical is expected to cause death in 50% of a defined experimental animal population. Lowest-Observed-Adverse-Effect Level (LOAEL) -- The lowest dose of chemical in a study, or group of studies, that produces statistically or biologically significant increases in frequency or severity of adverse effects between the exposed population and its appropriate control. Malformations -- Permanent structural changes that may adversely affect survival, development, or function. Minimal Risk Level -- An estimate of daily human exposure to a dose of a chemical that is likely to be without an appreciable risk of adverse noncancerous effects over a specified duration of exposure. Mutagen -- A substance that causes mutations. A mutation is a change in the genetic material in a body cell. Mutations can lead to birth defects, miscarriages, or cancer. Neurotoxicity -- The occurrence of adverse effects on the nervous system following exposure to chemical. No-Observed-Adverse-Effect Level (NOAEL) -- The dose of chemical at which there were no statistically or biologically significant increases in frequency or severity of adverse effects seen between the exposed population and its appropriate control. Effects may be produced at this dose, but they are not considered to be adverse. Octanol-Water Partition Coefficient (K,,) -- The equilibrium ratio of the concentrations of a chemical in n- octanol and water, in dilute solution. Permissible Exposure Limit (PEL) -- An allowable exposure level in workplace air averaged over an 8-hour shift. q,* -- The upper-bound estimate of the low-dose slope of the dose-response curve as determined by the multistage procedure. The q,* can be used to calculate an estimate of carcinogenic potency, the incremental excess cancer risk per unit of exposure (usually pg/L for water, mg/kg/day for food, and pg/m?® for air). 1238 9. GLOSSARY Reference Dose (RfD) -- An estimate (with uncertainty spanning perhaps an order of magnitude) of the daily exposure of the human population to a potential hazard that is likely to be without risk of deleterious effects during a lifetime. The RfD is operationally derived from the NOAEL (from animal and human studies) by a consistent application of uncertainty factors that reflect various types of data used to estimate RfDs and an additional modifying factor, which is based on a professional judgment of the entire database on the chemical. The RfDs are not applicable to nonthreshold effects such as cancer. Reportable Quantity (RQ) -- The quantity of a hazardous substance that is considered reportable under CERCLA. Reportable quantities are (1) 1 pound or greater or (2) for selected substances, an amount established by regulation either under CERCLA or under Sect. 311 of the Clean Water Act. Quantities are measured over a 24-hour period. Reproductive Toxicity -- The occurrence of adverse effects on the reproductive system that may result from exposure to a chemical. The toxicity may be directed to the reproductive organs and/or the related endocrine system. The manifestation of such toxicity may be noted as alterations in sexual behavior, fertility, pregnancy outcomes, or modifications in other functions that are dependent on the integrity of this system. Short-Term Exposure Limit (STEL) -- The maximum concentration to which workers can be exposed for up to 15 min continually. No more than four excursions are allowed per day, and there must be at least 60 min between exposure periods. The daily TLV-TWA may not be exceeded. Target Organ Toxicity -- This term covers a broad range of adverse effects on target organs or physiological systems (e.g., renal, cardiovascular) extending from those arising through a single limited exposure to those assumed over a lifetime of exposure to a chemical. Teratogen -- A chemical that causes structural defects that affect the development of an organism. Threshold Limit Value (TLV) -- A concentration of a substance to which most workers can be exposed without adverse effect. The TLV may be expressed as a TWA, as a STEL, or as a CL. Time-Weighted Average (TWA) -- An allowable exposure concentration averaged over a normal 8-hour workday or 40-hour workweek. Toxic Dose (TD) -- A calculated dose of a chemical, introduced by a route other than inhalation, which is expected to cause a specific toxic effect in 50% of a defined experimental animal population. Uncertainty Factor (UF) -- A factor used in operationally deriving the RfD from experimental data. UFs are intended to account for (1) the variation in sensitivity among the members of the human population, (2) the uncertainty in extrapolating animal data to the case of human, (3) the uncertainty in extrapolating from data obtained in a study that is of less than lifetime exposure, and (4) the uncertainty in using LOAEL data rather than NOAEL data. Usually each of these factors is set equal to 10. APPENDIX A USER'S GUIDE Chapter 1 Public Health Statement This chapter of the profile is a health effects summary written in nontechnical language. Its intended audience is the general public especially people living in the vicinity of a hazardous waste site or substance release. If the Public Health Statement were removed from the rest of the document, it would still communicate to the lay public essential information about the substance. The major headings in the Public Health Statement are useful to find specific topics of concern. The topics are written in a question and answer format. The answer to each question includes a sentence that will direct the reader to chapters in the profile that will provide more information on the given topic. Chapter 2 Tables and Figures for Levels of Significant Exposure (LSE) Tables (2-1, 2-2, and 2-3) and figures (2-1 and 2-2) are used to summarize health effects by duration of exposure and endpoint and to illustrate graphically levels of exposure associated with those effects. All entries in these tables and figures represent studies that provide reliable, quantitative estimates of No-Observed-Adverse-Effect Levels (NOAELSs), Lowest-Observed- Adverse-Effect Levels (LOAELSs) for Less Serious and Serious health effects, or Cancer Effect Levels (CELs). In addition, these tables and figures illustrate differences in response by species, Minimal Risk Levels (MRLs) to humans for noncancer end points, and EPA's estimated range associated with an upper-bound individual lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. The LSE tables and figures can be used for a quick review of the health effects and to locate data for a specific exposure scenario. The LSE tables and figures should always be used in conjunction with the text. The legends presented below demonstrate the application of these tables and figures. A representative example of LSE Table 2-1 and Figure 2-1 are shown. The numbers in the left column of the legends correspond to the numbers in the example table and figure. LEGEND See LSE Table 2-1 (1). Route of Exposure One of the first considerations when reviewing the toxicity of a substance using these tables and figures should be the relevant and appropriate route of exposure. When sufficient data exist, three LSE tables and two LSE figures are presented in the document. The three LSE tables present data on the three principal routes of exposure, i.e., inhalation, oral, and dermal (LSE Table 2-1, 2-2, and 2-3, respectively). LSE figures are limited to the inhalation (LSE Figure 2-1) and oral (LSE Figure 2-2) routes. (2). Exposure Duration Three exposure periods: acute (14 days or less); intermediate (15 to 364 days); and chronic (365 days or more) are presented within each route of exposure. In this example, an inhalation study of intermediate duration exposure is reported. 3). (4). (5). (6). . (8). 9). (10). (11). (12). A-2 APPENDIX A Health Effect The major categories of health effects included in LSE tables and figures are death, systemic, immunological, neurological, developmental, reproductive, and cancer. NOAELs and LOAELSs can be reported in the tables and figures for all effects but cancer. Systemic effects are further defined in the "System" column of the LSE table. Key to Figure Each key number in the LSE table links study information to one or more data points using the same key number in the corresponding LSE figure. In this example, the study represented by key number 18 has been used to define a NOAEL and a Less Serious LOAEL (also see the two "18r" data points in Figure 2-1). Species The test species, whether animal or human, are identified in this column. Exposure Frequency/Duration The duration of the study and the weekly and daily exposure regimen are provided in this column. This permits comparison of NOAELs and LOAELs from different studies. In this case (key number 18), rats were exposed to [substance x] via inhalation for 13 weeks, 5 days per week, for 6 hours per day. System This column further defines the systemic effects. These systems include: respiratory, cardiovascular, gastrointestinal, hematological, musculoskeletal, hepatic, renal, and dermal/ocular. "Other" refers to any systemic effect (e.g., a decrease in body weight) not covered in these systems. In the example of key number 18, one systemic effect (respiratory) was investigated in this study. NOAEL A No-Observed-Adverse-Effect Level (NOAEL) is the highest exposure level at which no harmful effects were seen in the organ system studied. Key number 18 reports a NOAEL of 3 ppm for the respiratory system which was used to derive an intermediate exposure. inhalation MRL of 0.005 ppm (see footnote "b"). LOAEL A Lowest-Observed-Adverse-Effect Level (LOAEL) is the lowest exposure level used in the study that caused a harmful health effect. LOAELs have been classified into "Less Serious" and "Serious" effects. These distinctions help readers identify the levels of exposure at which adverse health effects first appear and the gradation of effects with increasing dose. A brief description of the specific end point used to quantify the adverse effect accompanies the LOAEL. The "Less Serious" respiratory effect reported in key number 18 (hyperplasia) occurred at a LOAEL of 10 ppm. Reference The complete reference citation is given in Chapter 8 of the profile. CEL A Cancer Effect Level (CEL) is the lowest exposure level associated with the onset of carcinogenesis in experimental or epidemiological studies. CELs are always considered serious effects. The LSE tables and figures do not contain NOAELSs for cancer, but the text may report doses which did not cause a measurable increase in cancer. Footnotes Explanations of abbreviations or reference notes for data in the LSE tables are found in the footnotes. Footnote "b" indicates the NOAEL of 3 ppm in key number 18 was used to derive an MRL of 0.005 ppm. A-3 APPENDIX A LEGEND See LSE Figure 2-1 LSE figures graphically illustrate the data presented in the corresponding LSE tables. Figures help the reader quickly compare health effects according to exposure levels for particular exposure duration. (13). (14). (15). (16). (17). (18). (19). Exposure Duration The same exposure periods appear as in the LSE table. In this example, health effects observed within the intenmediate and chronic exposure periods are illustrated. Health Effect These are the categories of health effects for which reliable quantitative data exist. The same health effects appear in the LSE table. Levels of Exposure Exposure levels for each health effect in the LSE tables are graphically displayed in the LSE figures. Exposure levels are reported on the log scale "y" axis. Inhalation exposure is reported in mg/m’ or ppm and oral exposure is reported in mg/kg/day. NOAEL In this example, 18r NOAEL is the critical end point for which an intermediate inhalation exposure MRL is based. As you can see from the LSE figure key, the open-circle symbol indicates a NOAEL for the test species (rat). The key number 18 corresponds to the entry in the LSE table. The dashed descending arrow indicates the extrapolation from the exposure level of 3 ppm (see entry 18 in the Table) to the MRL of 0.005 ppm (see footnote "b" in the LSE table). CEL Key number 38r is one of three studies for which Cancer Effect Levels (CELs) were derived. The diamond symbol refers to a CEL for the test species (rat). The number 38 corresponds to the entry in the LSE table. Estimated Upper-Bound Human Cancer Risk Levels This is the range associated with the upper-bound for lifetime cancer risk of 1 in 10,000 to 1 in 10,000,000. These risk levels are derived from EPA’s Human Health Assessment Group's upper-bound estimates of the slope of the cancer dose response curve at low dose levels (q,"). Key to LSE Figure The Key explains the abbreviations and symbols used in the figure. ° WA ° ° ° * i XS i . . A O % sec eee ee elete 00 0 0" % % %" 1.8 8 8 200 0%’ [1] +> TABLE 2-1. Levels of Significant Exposure to [Chemical x] - Inhalation Exposure LOAEL (effect) Key to frequency/ NOAEL Less serious Serious figure® Species duration System (ppm) (ppm) (ppm) Reference }— INTERMEDIATE EXPOSURE 7 }— 18 Rat 13 wk Resp 3 10 (hyperplasia) Nitschke et al. 5d/wk 1981 6hr/d CHRONIC EXPOSURE Cancer bl 38 Rat 18 mo 20 (CEL, multiple Wong et al. 1982 5d/wk organs) Thr/d 39 Rat 89-104 wk 10 (CEL, lung tumors, NTP 1982 5d/wk nasal tumors) 6hr/d 40 Mouse 79-103 wk 10 (CEL, lung tumors, NTP 1982 5d/wk hemangiosarcomas) 6hr/d 2 The number corresponds to entries in Figure 2-1. [12}— b Used to derive an intermediate inhalation Minimal Risk Level (MRL) of 5 x 1073 ppm; dose adjusted for intermittent exposure and divided by an uncertainty factor of 100 (10 for extrapolation from animal to humans, 10 for human variability). CEL = cancer effect level; d = day(s); hr = hour(s); LOAEL = lowest-observed-adverse-effect level; mo = month(s); NOAEL = no- observed-adverse-effect level; Resp = respiratory; wk = week(s) V XION3ddv v-v [3] ———— + INTERMEDIATE (15-364 Days) (2368 Days) Byetomis Systane [@--- & J Ss s Ars 0 Ls 1.000 } 100 l@e ®1» Buse Ow Gog GeO» on On Oma Bre Dse (Pree Ore - wl "ow 0 0m On Om Om Ow Om On On Om $2 id [16 — sw 3 c— > Qe Or } , [] 0 3 104 oor | ' 10S Hound Human 0 Cancer Rish ooor | 3S Rey 108 down + Au © 10AFL tr seme effects jardraaty) * eco0r | m Mase @ 10AEL tur ose soins Shioum fardmats) ) Meenas 10-7 » Rasa O woAtl jwtmany | oflern che hen cance 20s On ’ Gutnsasy @ cet Canon Efect Love! ~ -— —{w he rumber nest to each paint con cepands to entries br Tetse 2 § * Doses repvesers vo lowes! $0se tested por shady rat produpnd © humadgenic 100pantt tnd 0 BE Imply Tro teh rE of © Sr oehetd br Bu sence end pebvl FIGURE 2-1. Levels of significant Exposure to [Chemical X]-Inhalation V XIGN3ddV Sv A-6 APPENDIX A Chapter 2 (Section 2.4) Relevance to Public Health The Relevance to Public Health section provides a health effects summary based on evaluations of existing toxicological, epidemiological, and toxicokinetic information. This summary is designed to present interpretive weight-of-evidence discussions for human health end points by addressing the following questions. 1. What effects are known to occur in humans? 2. What effects observed in animals are likely to be of concern to humans? 3 What exposure conditions are likely to be of concern to humans, especially around hazardous waste sites? The section discusses health effects by end point. Human data are presented first, then animal data. Both are organized by route of exposure (inhalation, oral, and dermal) and by duration (acute, intermediate, and chronic). In vitro data and data from parenteral routes (intramuscular, intravenous, subcutaneous, etc.) are also considered in this section. If data are located in the scientific literature, a table of genotoxicity information is included. The carcinogenic potential of the profiled substance is qualitatively evaluated, when appropriate, using existing toxicokinetic, genotoxic, and carcinogenic data. ATSDR does not currently assess cancer potency or perform cancer risk assessments. MRLs for noncancer end points if derived, and the end points from which they were derived are indicated and discussed in the appropriate section(s). Limitations to existing scientific literature that prevent a satisfactory evaluation of the relevance to public health are identified in the Identification of Data Needs section. Interpretation of Minimal Risk Levels Where sufficient toxicologic information was available, MRLs were derived. MRLs are specific for route (inhalation or oral) and duration (acute, intermediate, or chronic) of exposure. Ideally, MRLs can be derived from all six exposure scenarios (e.g., Inhalation - acute, -intermediate, -chronic; Oral - acute, -intermediate, - chronic). These MRLs are not meant to support regulatory action, but to aquaint health professionals with exposure levels at which adverse health effects are not expected to occur in humans. They should help physicians and public health officials determine the safety of a community living near a substance emission, given the concentration of a contaminant in air or the estimated daily dose received via food or water. MRLs are based largely on toxicological studies in animals and on reports of human occupational exposure. MRL users should be familiar with the toxicological information on which the number is based. Section 2.4, "Relevance to Public Health," contains basic information known about the substance. Other sections such as 2.6, “Interactions with Other Chemicals” and 2.7, "Populations that are Unusually Susceptible” provide important supplemental information. MRL users should also understand the MRL derivation methodology. MRLs are derived using a modified version of the risk assessment methodology used by the Environmental Protection Agency (EPA) (Barnes and Dourson, 1988: EPA 1989a) to derive reference doses (RfDs) for lifetime exposure. A-7 APPENDIX A To derive an MRL, ATSDR generally selects the end point which. in its best judgement, represents the most sensitive human health effect for a given exposure route and duration. ATSDR cannot make this judgement or derive an MRL unless information (quantitative or qualitative) is available for all potential effects (e.g., systemic, neurological, and developmental). In order to compare NOAELs and LOAELS for specific end points, all inhalation exposure levels are adjusted for 24hr exposures and all intermittent exposures for inhalation and oral routes of intermediate and chronic duration are adjusted for continous exposure (i.c., 7 days/week). If the information and reliable quantitative data on the chosen end point are available, ATSDR derives an MRL using the most sensitive species (when information from multiple species is available) with the highest NOAEL that does not exceed any adverse effect levels. The NOAEL is the most suitable end point for deriving an MRL. When a NOAEL is not available, a Less Serious LOAEL can be used to derive an MRL, and an uncertainty factor (UF) of 10 is employed. MRLs are not derived from Serious LOAELs. Additional uncertainty factors of 10 each are used for human variability to protect sensitive subpopulations (people who are most susceptible to the health effects caused by the substance) and for interspecies variability (extrapolation from animals to humans). In deriving an MRL, these individual uncertainty factors are multiplied together. The product is then divided into the adjusted inhalation concentration or oral dosage selected from the study. Uncertainty factors used in developing a substance-specific MRL are provided in the footnotes of the LSE Tables. ACGIH ADME atm ATSDR BCF BSC C CDC CEL CERCLA CFR CLP cm CNS d DHEW DHHS DOL ECG EEG EPA EKG F F, FAO FEMA FIFRA fpm ft FR g GC gen HPLC hr IDLH IARC ILO in Kd kg kkg K Kon L oC B-1 APPENDIX B ACRONYMS, ABBREVIATIONS, AND SYMBOLS American Conference of Governmental Industrial Hygienists Absorption, Distribution, Metabolism, and Excretion atmosphere Agency for Toxic Substances and Disease Registry bioconcentration factor Board of Scientific Counselors Centigrade Centers for Disease Control Cancer Effect Level Comprehensive Environmental Response, Compensation, and Liability Act Code of Federal Regulations Contract Laboratory Program centimeter central nervous system day Department of Health, Education, and Welfare Department of Health and Human Services Department of Labor electrocardiogram electroencephalogram Environmental Protection Agency see ECG Fahrenheit first filial generation Food and Agricultural Organization of the United Nations Federal Emergency Management Agency Federal Insecticide, Fungicide, and Rodenticide Act feet per minute foot Federal Register gram gas chromatography generation high-performance liquid chromatography hour Immediately Dangerous to Life and Health International Agency for Research on Cancer International Labor Organization inch adsorption ratio kilogram metric ton organic carbon partition coefficient octanol-water partition coefficient liter LC LC, LCi LDy, LOAEL LSE mg min mL mm mmHg mmol mo mppcf MS NIEHS NIOSH NIOSHTIC ng nm nmol NOAEL NOES NOHS NRC NTIS OSHA PEL pg pmol PHS PMR ppb ppm ppt REL RfD RTECS sec SCE SIC SMR B-2 APPENDIX B liquid chromatography lethal concentration, low lethal concentration, 50% kill lethal dose, low lethal dose, 50% kill lowest-observed-adverse-effect level Levels of Significant Exposure meter milligram minute milliliter millimeter millimeters of mercury millimole month millions of particles per cubic foot Minimal Risk Level mass spectrometry National Institute of Environmental Health Sciences National Institute for Occupational Safety and Health NIOSH’s Computerized Information Retrieval System nanogram nanometer National Health and Nutrition Examination Survey nanomole no-observed-adverse-effect level National Occupational Exposure Survey National Occupational Hazard Survey National Priorities List National Research Council National Technical Information Service National Toxicology Program Occupational Safety and Health Administration permissible exposure limit picogram picomole Public Health Service proportionate mortality ratio parts per billion parts per million parts per trillion recommended exposure limit Reference Dose Registry of Toxic Effects of Chemical Substances second sister chromatid exchange Standard Industrial Classification standard mortality ratio STEL STORET TLV TSCA oR KINA IVY EER ® 3 0 B-3 APPENDIX B short term exposure limit STORAGE and RETRIEVAL threshold limit value Toxic Substances Control Act Toxics Release Inventory time-weighted average United States uncertainty factor year World Health Organization week greater than greater than or equal to equal to less than less than or equal to percent alpha beta delta gamma micron microgram C-1 APPENDIX C PEER REVIEW A peer review panel was assembled for cyanide. The panel consisted of the following members: Dr. Gary Isom, Professor of Toxicology, Department of Pharmacology and Toxicology, Purdue University, West Lafayette, Indiana; Dr. Roger Smith, Professor of Pharmacology and Toxicology, Dartmouth Medical School, Hanover, New Hampshire; Dr. James Way, Professor of Pharmacology and Toxicology, College of Medicine, Texas A&M University, College Station, Texas; Dr. Brent Burton, Associate Professor of Emergency Medicine, Oregon Poison Center, Oregon Health Sciences University, Portland, Oregon; Dr. Frederick Oehme, Director, Comparative Toxicology Laboratories, Kansas State University, Manhattan, Kansas; Dr. Joseph Borowitz, Professor of Pathology, Department of Pharmacology & Toxicology, School of Pharmacy and Pharmacal Sciences, Purdue University, West Lafayette, Indiana; Dr. Peter Lacouture, Associate Director, Clinical Research, The Purdue Frederick Company, Norwalk, Connecticut; and Dr. Rolf Hartung, Professor of Environmental Toxicology, Department of Environmental & Industrial Health, University of Michigan, Ann Arbor, Michigan. These experts collectively have knowledge of cyanide’s physical and chemical properties, toxicokinetics, key health end points, mechanisms of action, human and animal exposure, and quantification of risk to humans. All reviewers were selected in conformity with the conditions for peer review specified in Section 104(i)(13) of the Comprehensive Environmental Response, Compensation, and Liability Act, as amended. Scientists from the Agency for Toxic Substances and Disease Registry (ATSDR) have reviewed the peer reviewers’ comments and determined which comments will be included in the profile. A listing of the peer reviewers’ comments not incorporated in the profile, with a brief explanation of the rationale for their exclusion, exists as part of the administrative record for this compound. A list of databases reviewed and a list of unpublished documents cited are also included in the administrative record. The citation of the peer review panel should not be understood to imply its approval of the profile’s final content. The responsibility for the content of this profile lies with the ATSDR. vr U.S. GOVERNMENT PRINTING OFFICE: 1993 738-201 U. C. BERKELEY LIBRARIES CO4435458k